Nanotechnology in Prostate Cancer: PSMA-Targeted Nanoplatforms, TME-Responsive Therapy, Immunomodulation, and Clinical Translation Challenges.

Introduction

Prostate cancer is among the most prevalent malignancies affecting the male urinary system. 1 , 2 On a global scale, this type of cancer ranks second in incidence and fifth in mortality among male cancers. 3 According to GLOBOCAN 2022 data, approximately 1.47 million new cases of prostate cancer were diagnosed worldwide in 2022, resulting in approximately 390,000 deaths. 3 The risk of developing prostate cancer increases significantly with age. The high detection rate of prostate cancer can be attributed to two major factors: population aging and the widespread adoption of prostate-specific antigen (PSA) screening. However, these factors have also given rise to issues of overdiagnosis and overtreatment. 2 , 4 The PSA test is the most widely used method for prostate cancer screening. However, the test has limited specificity, which hinders its ability to distinguish indolent from aggressive cancers effectively. As a result, a significant number of low-risk patients undergo unnecessary prostate biopsies or curative treatments. 5 Moreover, for patients diagnosed with locally advanced or metastatic prostate cancer, androgen deprivation therapy (ADT) is the standard initial treatment; however, most patients eventually progress to castration-resistant prostate cancer (CRPC). 6 , 7 Treatment options for CRPC patients are limited. While traditional chemotherapy drugs, such as docetaxel, can prolong survival, they carry significant systemic toxicity and are prone to multidrug resistance with long-term use. This is primarily due to the complexity of resistance-related signaling pathways and the tumor microenvironment. 8 Consequently, the development of novel diagnostic and therapeutic strategies with higher specificity, lower toxicity, and the ability to overcome drug resistance has become an urgent need in prostate cancer clinical research.

Prostate cancer is characterized by significant molecular heterogeneity, with frequent alterations in the androgen receptor (AR) signaling axis, PTEN-PI3K-AKT pathway, and DNA repair genes (eg, BRCA1/2, ATM), including TMPRSS2-ERG fusions (50–70% of primary tumors), PTEN loss (20–40% localized, up to 60% metastatic CRPC), and TP53/RB1 mutations that drive aggressive phenotypes and therapeutic resistance. 9–13 Disease progression to metastatic CRPC involves AR amplification, androgen receptor splice variant 7 (AR-V7) expression, and bypass signaling, all within a bone-predominant metastatic niche (>90%) that promotes tumor survival and further resistance. 14–16 Despite therapeutic options such as docetaxel, cabazitaxel, abiraterone, enzalutamide, 223 Ra, and sipuleucel-T, durable responses remain limited, with median resistance emerging within 12–18 months and only modest survival extensions, while the immunologically “cold” microenvironment limits checkpoint inhibitor efficacy. 17–22 These treatment gaps are compounded by the inadequacy of PSA monitoring and the impracticality of tissue biopsies in metastatic disease, prompting the need for nanotechnology-enhanced liquid biopsy to enable real-time molecular profiling and resistance mutation monitoring. 15 , 23 Together, these prostate cancer-specific features—well-defined surface targets (prostate-specific membrane antigen [PSMA], prostate stem cell antigen [PSCA], six-transmembrane epithelial antigen of prostate 1 [STEAP1]), the unique biological barriers of bone metastases, complex resistance pathways, and the chronic disease course—establish prostate cancer as an ideal model for developing nanoplatforms capable of overcoming these challenges through targeted delivery, microenvironment modulation, and long-term safety. 16 , 24 , 25

The term “nanotechnology” refers to the manipulation of materials’ properties and structures at the nanoscale (typically 1–100 nm) to create functional systems with unique physical, chemical, or biological characteristics. When material dimensions are reduced to the nanoscale, their specific surface area increases significantly, surface activity is enhanced, and properties not found in macroscopic materials—such as quantum confinement effects—may emerge. It is evident that, given these characteristics, the use of nanoparticles as drug carriers or molecular probes signifies a wide range of potential applications in the biomedical field. 26 In the context of cancer diagnosis and treatment, nanoparticles can achieve targeted accumulation through two primary mechanisms. The first is passive targeting, which exploits the high permeability and retention properties of solid tumors (the enhanced permeability and retention [EPR] effect). The incomplete structure of tumor vasculature and impaired lymphatic drainage can permit selective extravasation and accumulation of nanoparticles within tumor tissue. 27 , 28 The second mechanism is active targeting, which involves modifying the nanoparticle surface with specific ligands (such as antibodies, peptides, aptamers, or small-molecule inhibitors) to enable specific binding to receptors overexpressed on the surface of tumor cells (such as PSMA). This further enhances delivery efficiency and cellular uptake. 29 Additionally, nanoparticles can be engineered to respond to external physical stimuli, such as heat, light, or magnetic fields, or internal signals within the tumor microenvironment, including low pH, high enzyme concentrations, or redox gradients. This enables spatiotemporally controlled drug release. 30 , 31 These characteristics position nanotechnology as a promising approach to overcoming the inherent limitations of traditional small-molecule drugs, including poor pharmacokinetics, lack of distribution selectivity, and narrow therapeutic windows.

In addition to synthetic nanocarrier systems, the integration of nanotechnology with natural bioactive compounds and sustainable synthesis methodologies has emerged as an environmentally conscious approach to developing biocompatible nanoplatforms for cancer theranostics. Green nanotechnology employs agricultural waste products and plant extracts as reducing and stabilizing agents for nanoparticle synthesis, offering advantages including cost-effectiveness, reduced environmental toxicity, and enhanced biocompatibility. For instance, zinc sulfide nanoparticles synthesized using banana peel extracts have demonstrated remarkable photocatalytic and antioxidant properties, suggesting their potential as biocompatible nanocarriers or exosome mimics for drug delivery applications. 32 Similarly, selenium nanoparticles derived from potato peel extracts demonstrate significant cytotoxic and antimicrobial activity, which may be leveraged to regulate oxidative stress and modulate immune responses within the tumor microenvironment. 33 The sustainable synthesis of palladium and platinum nanoparticles using mung bean (Vigna radiata L). extracts enables efficient metal recycling while maintaining functional bioactivity, demonstrating the feasibility of eco-friendly approaches for surface modification of therapeutic nanoparticles in precision oncology. 34 Furthermore, silver nanoparticles biosynthesized from agricultural byproducts, such as sumac (Rhus coriaria L)., have been shown to possess effective antimicrobial properties. These properties could be leveraged to design antimicrobial-resistant surfaces for implantable nanoplatforms. 35 These green synthesis strategies not only address biocompatibility and environmental concerns but also offer novel bioactive functionalities that may complement existing prostate cancer nanomedicine approaches.

This narrative review is based on a comprehensive literature search of the PubMed, Web of Science, and Scopus databases. The search was conducted using combinations of keywords including “prostate cancer”, “nanotechnology”, “nanoparticle”, “PSMA targeting”, “theranostic”, “drug delivery”, “clinical trial”, and “translational medicine”. The search covered publications from January 2010 through June 2026, with emphasis on high-impact original research, preclinical studies with translational relevance, and clinical trials. To capture additional relevant studies, reference lists of identified articles were also manually screened. Given the broad and rapidly evolving nature of the field, this narrative synthesis was chosen to provide an integrated perspective on the diverse applications of nanotechnology in prostate cancer, with emphasis on representative platforms, key mechanisms, and translational challenges rather than exhaustive enumeration of all published studies.

The objective of this review is to provide a concise overview of the current state of nanotechnology applications in prostate cancer. The review will focus on the following key points: (1) Diagnostic nanotechnologies—nanoprobes for molecular imaging (MRI, optical, multimodal) and liquid biopsy nanosensors for the detection of circulating tumor cells, exosome, and circulating tumor DNA; (2) Therapeutic nanomedicine delivery systems—nanocarriers for chemotherapy, gene therapy (siRNA, CRISPR/Cas9), immunotherapy, and combination therapy, with an emphasis on active targeting (PSMA and other ligands) and tumor microenvironment (TME)-responsive release mechanisms; (3) Integrated theranostic nanoplatforms—multifunctional systems combining imaging and therapeutic functions for real-time efficacy assessment and personalized treatment; and (4) Clinical translation analysis—critical evaluation of nanomedicines that have entered clinical trials, major translational barriers (biological, safety, manufacturing, regulatory), and future directions for overcoming these challenges. Additionally, this paper will analyze the major challenges facing nanotechnology in the clinical translation of prostate cancer and outline potential future directions, to provide a reference for researchers working at the intersection of nanomedicine and prostate cancer.

Applications of Nanotechnology in Prostate Cancer Diagnosis and Imaging

Nanoparticle-Based Molecular Imaging

In the context of prostate cancer imaging, nanoparticles serve as molecular probes, thereby enhancing the sensitivity and specificity for detecting tumor lesions, with particular emphasis on micrometastases and lymph node metastases. 36 In MRI, superparamagnetic iron oxide (SPIO) and ultra-small superparamagnetic iron oxide (USPIO) nanoparticles have been the focus of extensive research. 37–39 The nanoparticle uptake by the reticuloendothelial system leads to signal attenuation in normal lymph nodes. In contrast, metastatic lymph nodes exhibit unaltered signal intensity due to the disruption of normal structures, facilitating the distinction between tumor infiltration and reactive hyperplasia. 37–39 For primary prostate cancer lesions, SPIO nanoprobes targeting PSMA can actively localize to and enhance T2/T2*-negative contrast in tumor regions, thereby improving MRI diagnostic accuracy. 40 In the domain of optical imaging, quantum dots (QDs) and near-infrared fluorescence (NIRF) nanoprobes are employed for intraoperative guidance due to their high brightness, photostability, and deep tissue penetration. 41–43 In preclinical studies, PSMA-targeted near-infrared fluorescent nanomicelles have the potential to facilitate real-time visualization of the margins of prostate cancer tumors in animal models. This could assist surgeons in completely resecting tumors while preserving surrounding nerves during radical surgery. 42 , 43 Furthermore, gold nanoparticles, carbon nanotubes, and rare-earth-doped nanoparticles have been identified as suitable substrates for fluorescence or surface-enhanced Raman scattering (SERS) imaging, thereby facilitating the acquisition of molecular information with sub-cellular spatial resolution. 44 To overcome the limitations of single imaging modalities, researchers have developed multimodal nanoprobes, such as nanoparticles simultaneously loaded with radionuclides, MRI contrast agents, or fluorescent dyes, enabling multimodal imaging. 45–47 These probes offer a comprehensive approach to drug testing, providing quantitative pharmacokinetic data through PET and high-resolution anatomical information through MRI. Furthermore, these devices can guide precise resection during surgery using fluorescent signals, demonstrating their potential for preoperative staging and intraoperative decision-making in prostate cancer.

Liquid Biopsy and Nanosensors

Liquid biopsy is a non-invasive method for the early diagnosis, treatment monitoring, and prognosis assessment of prostate cancer. It is a process that detects circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and exosomes in bodily fluids such as blood and urine. 23 The application of nanotechnology has the potential to enhance the efficacy of liquid biopsy by improving capture efficiency and detection sensitivity. 48 , 49 With respect to the capture of CTCs, microfluidic chips based on nanostructures—such as nanocolumns, nanowires, and nano-roughened surfaces—have been shown to enrich CTCs at low abundances efficiently. This is achieved by increasing the probability of contact between the topological structure and the microvilli on the CTC surface. This process is further enhanced by modifying the microfluidic chips with anti-EpCAM or anti-PSMA antibodies. 50 , 51 For instance, magnetic nanoparticles have been shown to detect multiple CTCs per milliliter in blood samples from patients with prostate cancer. These nanoparticles exhibit superior capture purity and cell viability compared to conventional membrane filtration methods. 52 A bait-trap chip that integrates nanocage structures with branched aptamers has demonstrated high diagnostic sensitivity (100%) and specificity (86%) for the early detection of prostate cancer. The chip has also shown approximately 95% accuracy in capturing living CTCs from peripheral blood. 53 In the domain of exosome detection, nanosensors leverage the principles of surface plasmon resonance (SPR), electrochemical impedance spectroscopy, or localized surface plasmon resonance (LSPR). The use of gold or magnetic nanoparticles in the labeling process enhances the sensitivity of quantification of surface proteins (eg, PSMA and STEAP1) and of internal nucleic acids. 54 , 55 A conventional strategy involves immobilizing anti-CD63 antibodies on a gold membrane, using gold nanoparticles to amplify the SPR signal. This approach facilitates the detection of exosome samples at concentrations as low as 10 4 –10 5 per microliter. 55 For free nucleic acids, including the TMPRSS2-ERG fusion gene present in ctDNA, nanopore-based single-molecule sequencing or hybridization detection methods employing electrochemical nanobiosensors can detect mutations without amplification or with minimal amplification, achieving femtomolar detection limits. 56 A label-free plasmonic metasensing platform functionalized with anti-PSA and anti-CD63 antibodies can discriminate early prostate cancer from benign prostatic hyperplasia with a diagnostic sensitivity of 92.3%—substantially higher than the 58.3% sensitivity of conventional PSA tests—with an area under the curve (AUC) of 99.4%. 57 The utilization of nanosensors confers several advantages, including rapid response, minimal sample consumption, and seamless integration and miniaturization. These sensors are anticipated to be used for early screening of prostate cancer and monitoring of drug-resistant mutations in CRPC ( Figure 1 ). Figure 1 Nanoprobes for multimodal imaging and liquid biopsy in prostate cancer. (Top) PSMA-targeted multifunctional nanoparticles enable three complementary imaging modalities: PET for whole-body tumor staging with high sensitivity; MRI for high-resolution anatomical localization; and NIRF for intraoperative real-time fluorescence guidance. PSMA ligand-mediated active targeting ensures selective accumulation in PSMA-expressing tumor cells via receptor-mediated endocytosis. (Bottom) Nanostructured chips fabricated with nanowire/nanocolumn substrates and functionalized with capture antibodies (anti-EpCAM, anti-PSMA) enable simultaneous capture of three liquid biopsy analytes from blood or urine: CTCs (intact tumor cells for enumeration and phenotyping), exosomes (30–150 nm vesicles rich in tumor-derived proteins and RNAs for early detection and resistance prediction), and ctDNA (tumor-derived DNA fragments for genotyping and mutation monitoring). These technologies collectively support preoperative staging, intraoperative guidance, non-invasive early diagnosis, treatment monitoring, and detection of resistance mutations. The diagram illustrates multimodal imaging and liquid biopsy techniques for prostate cancer. Multimodal imaging includes MRI for high-resolution anatomical localization, PET for whole-body tumor staging and NIRF for real-time fluorescence guidance. These modalities utilize multimodal nanoprobes. Liquid biopsy involves blood and urine samples analyzed using nano-microfluidic chips and gold nanoparticles. The chips capture circulating tumor cells (CTCs) for enumeration and phenotyping, while ctDNA is used for genotyping and mutation monitoring. Exosomes are analyzed for early detection and resistance prediction. The diagram highlights the integration of these technologies for comprehensive cancer diagnosis and monitoring. Diagram of multimodal imaging and liquid biopsy for prostate cancer using MRI, PET, NIRF and nanoprobes. Abbreviations : CTC, circulating tumor cell; ctDNA, circulating tumor DNA; EpCAM, epithelial cell adhesion molecule; MRI, magnetic resonance imaging; NIRF, near-infrared fluorescence; PET, positron emission tomography; PSMA, prostate-specific membrane antigen.

Liquid biopsy strategies for prostate cancer can be logically categorized according to analyte type, sample source, detection technology, and clinical application. Each category offers distinct advantages and limitations for different stages of disease management. 58 , 59 CTCs are defined as intact tumor cells captured from peripheral blood using immunocapture techniques that employ anti-EpCAM/PSMA antibodies combined with nanostructured substrates or magnetic nanoparticles. These cells permit enumeration, phenotyping, and functional analysis, exhibiting clinical utility in prognosis (CTC count correlates with survival in metastatic castration-resistant prostate cancer [mCRPC]), treatment monitoring (dynamic changes reflect response), and patient selection (CTC-based PSMA expression may identify candidates for PSMA-targeted therapies). 60 , 61 However, their low abundance in early disease and the challenges associated with their isolation limit sensitivity. ctDNA is defined as tumor-derived DNA fragments in plasma or serum that PCR, next-generation sequencing, or nanopore sequencing detect. It enables genotyping (TMPRSS2-ERG, AR mutations, BRCA1/2), resistance monitoring (AR-V7 detection), and tumor burden assessment. ctDNA offers the advantages of being relatively abundant, non-invasive, and reflective of tumor heterogeneity. 62–64 However, it requires tumor-derived mutations for tracking and has lower sensitivity in the presence of a disease within a localized region. Exosomes are defined as 30–150 nanometer-sized extracellular vesicles that are present in high concentrations in blood and urine (104–105/microliter). They can be detected using immunoaffinity capture techniques, such as anti-CD63, anti-PSMA, and anti-STEAP1, with SPR or nanoparticle-amplified detection methods. 55 These vesicles contain a diverse molecular cargo, including proteins and RNAs, and they facilitate early diagnosis, treatment monitoring, and resistance prediction in cancer. 65 Specifically, exosomal PSMA and STEAP1 expression may surpass the sensitivity of PSA detection, while the presence of exosomal AR-V7 mRNA can indicate treatment resistance. 66 , 67 However, the isolation, purification, and standardization of these vesicles remain significant challenges in clinical research and practice. Collectively, these analytes offer complementary information: CTCs offer the most precise molecular data but are present in the lowest concentrations. ctDNA provides the most direct indication of genomic alterations and is well-suited for resistance mutation monitoring. Exosomes represent the most plentiful source of tumor-derived proteins and RNAs, making them appealing for early detection and serial monitoring. The optimal strategy is contingent upon the clinical question at hand, whether it pertains to the early detection of exosome or ctDNA, the identification of genomic resistance mutations through ctDNA analysis, the detection of protein markers such as AR-V7 through CTCs or exosome analysis, or the implementation of combined approaches for comprehensive treatment monitoring. However, it should be noted that the technical integration of multi-analyte platforms remains a significant challenge. 68

Ultra-Sensitive Detection at the Pathological Level

At the histopathological level, traditional immunohistochemistry (IHC) and in situ hybridization (ISH) techniques are limited by insufficient sensitivity and signal attenuation due to photobleaching of organic dyes, making it difficult to meet the demands of precision diagnosis of prostate cancer, which requires detecting trace targets and performing multi-parameter analysis. 69 The use of functionalized nanoparticles as signal-amplification elements in pathological detection has emerged as a state-of-the-art strategy to address these limitations. 70 The use of QDs, which exhibit a broad excitation spectrum, a narrow emission spectrum, and remarkable photobleaching resistance, enables concurrent, highly sensitive imaging of multiple markers, including E-cadherin and p63, on a single paraffin section. As the data indicate, signal retention remains above 93% four weeks post-labeling. 71 In addition, multiplex ISH technology has been shown to simultaneously assess the gene status of ERG and PTEN with a 91% success rate. 72 Gold nanoparticles loaded with a large amount of horseradish peroxidase utilize the synergistic amplification of DAB color development signals by combining enzymatic activity with SPR. This approach is predicated on enzyme-catalyzed enhanced dark-field imaging, a technique that enables semi-quantitative analysis of target proteins. 73 SERS nanoprobes, using nanoimprinting technology, can concurrently detect tissue acidity and PSA activity, thereby facilitating rapid and precise grading of prostate cancer. 44 Furthermore, the tyramine signal amplification (TSA) system achieves cascade amplification through the enzymatic deposition of labeled tyramine molecules, and a seven-color multiplex immunofluorescence protocol for single-slide analysis has been developed. 74 Due to their small molecular weight and strong tissue permeability, nanobodies can improve labeling density and three-dimensional imaging quality in thick sections. 75 , 76

Applications of Nanotechnology in Prostate Cancer Treatment

Nanomedicine Delivery Systems

The use of nanomedicine delivery systems has been shown to enhance the pharmacokinetic profile of conventional anticancer drugs. This enhancement includes prolongation of the drug’s circulation half-life, increased accumulation at the tumor site, and reduced systemic toxic side effects. In the domain of prostate cancer treatment research, a range of nanocarriers have been documented, predominantly comprising liposomes, polymeric nanoparticles, and inorganic nanoparticles.

Liposomes were among the first types of nanocarriers to enter clinical use. Polyethylene glycol (PEG)-conjugated liposomes have been shown to prolong drug circulation by reducing recognition and clearance by the reticuloendothelial system. 77 Doxorubicin hydrochloride liposomes (eg, Doxil ® /Caelyx ® ) have been approved for the treatment of ovarian cancer and multiple myeloma, among other indications. In the context of preclinical and clinical studies of prostate cancer, these agents have also been evaluated for their efficacy in treating CRPC. The results of the study suggest that they can mitigate the cardiotoxicity of doxorubicin; however, their efficacy is limited, potentially due to inefficient drug release within tumor tissue. 78 , 79 To enhance treatment precision, researchers have developed a new class of liposomes modified with specific ligands, such as those conjugated to anti-PSMA antibodies. These modified liposomes have been shown to exhibit higher rates of tumor suppression compared with conventional liposomes. 80

Polymer nanoparticles represent another extensively studied category of carriers. Polylactic-co-glycolic acid (PLGA) is used to encapsulate chemotherapeutic drugs, including docetaxel and cabazitaxel, due to its remarkable biocompatibility and degradability. 81 The rate of drug release can be modulated by adjusting the molecular weight of PLGA and the lactide/glycolide ratio. 82 Furthermore, dendrimers, including polyamidoamine (PAMAM), are characterized by highly branched, three-dimensional structures and surface functional groups amenable to modification. These properties render them well-suited for the delivery of chemotherapeutic agents, nucleic acids, or imaging agents. 83 , 84 For instance, PAMAM-based carriers loaded with camptothecin and conjugated with PSMA-targeting ligands have exhibited remarkable therapeutic efficacy in prostate cancer models. This enhancement is attributed to the increased solubility, intracellular release, and PSMA-positive tumor-specific toxicity of the carriers. 85

The use of inorganic nanoparticles in the treatment of prostate cancer is primarily focused on photothermal and photodynamic therapies. Gold nanoshells (Au nanoshells) and gold nanorods (Au nanorods) possess strong near-infrared absorption capabilities, enabling the conversion of light energy into thermal energy. This process leads to localized temperature elevation, which in turn induces tumor cell apoptosis or necrosis. 86 AuroShell ® , a product based on gold nanoshells, has undergone clinical trials for photothermal therapy in patients with prostate cancer. These trials have demonstrated that the product is both feasible and safe in low- or intermediate-risk localized prostate cancer cases. 87 , 88 A high specific surface area, tunable pore sizes, and good thermal stability characterize mesoporous silica nanoparticles (MSN). The platform’s ability to simultaneously load chemotherapeutic agents and photosensitizers enables the implementation of a combined chemotherapeutic-photothermal therapeutic modality. 89 , 90 Furthermore, magnetic nanoparticles have been utilized in prostate cancer research due to their magnetotherapeutic properties, which enable them to generate thermal effects in alternating magnetic fields, and their potential for integrated diagnosis and treatment. 91 , 92 For instance, a study developed an exosome platform loaded with superparamagnetic iron oxide nanoparticles (SPIONs). It used magnetic particle imaging (MPI) for tracking, thereby achieving magnetothermal therapy in a mouse model of prostate cancer. 92

Selecting an appropriate nanocarrier system for prostate cancer therapy requires careful consideration of the therapeutic payload, target site, disease stage, and clinical context. Liposomes are the most clinically mature platform, offering the advantage of established safety profiles and manufacturing processes, making them suitable for rapid clinical translation of chemotherapy regimens. 93 However, their limited tumor penetration and inefficient intracellular drug release have prompted the development of stimulus-responsive liposomal formulations. 94 Polymeric nanoparticles offer enhanced flexibility in release kinetics and drug loading capacity, with PLGA-based systems facilitating sustained release over weeks to months. This feature is particularly advantageous for long-term adjuvant therapy in prostate cancer. 94 , 95 Dendrimers, with their precisely defined architecture and multivalent surface functionality, offer unique advantages for nucleic acid delivery and targeted imaging. 96 , 97 However, their clinical translation has been constrained by manufacturing complexity and potential toxicity concerns. 97 Inorganic nanoparticles offer unparalleled physical properties for photothermal and photodynamic therapy. 98 However, there are substantial hurdles related to long-term biocompatibility and regulatory approval. Their non-biodegradable nature raises concerns about chronic accumulation and organ toxicity. 99 , 100 For nucleic acid-based therapies—including siRNAs, mRNA vaccines, and CRISPR/Cas9 systems—lipid nanoparticles currently represent the most advanced platform, building upon the clinical success of LNP-formulated mRNA vaccines for the prevention of severe acute respiratory syndrome (SARS-CoV-2). 101 The choice of carrier represents a trade-off between clinical maturity (liposomes, lipid nanoparticles [LNPs]), functional versatility (polymeric nanoparticles), and unique therapeutic capabilities (inorganic nanoparticles for photothermal therapy). Emerging strategies that combine multiple carrier types—such as polymer-coated inorganic nanoparticles or lipid-polymer hybrid systems—aim to harness the advantages of each platform while mitigating their respective limitations. 102

Targeting Strategies

To enhance the selective accumulation of nanomedicines in prostate cancer lesions and improve therapeutic efficacy, researchers have designed various active targeting strategies and delivery systems that are responsive to the tumor microenvironment. Among the various active targeting ligands developed, those targeting PSMA have garnered the most attention. 24 , 103 PSMA is expressed at high levels on the cell membrane of prostate cancer cells. Its expression levels are further elevated in CRPC and metastatic lesions, while expression in normal tissues is limited. This characteristic makes PSMA an ideal target for therapeutic intervention. 24 , 25 PSMA-targeting ligands used to modify nanoparticles include anti-PSMA monoclonal antibodies (eg, J591), 104 their antigen-binding fragments (Fab), 105 small-molecule inhibitors (eg, DUPA), 106 and nucleic acid aptamers (eg, A10). 107 Among these, small-molecule inhibitors are widely used for their stability, low immunogenicity, and ease of chemical synthesis. For instance, polymeric nanoparticles modified with DUPA and loaded with docetaxel have been shown to exhibit higher intracellular uptake and stronger antineoplastic activity in PSMA-positive prostate cancer models compared with non-targeted particles. 108 Furthermore, targeting peptides directed against the AR and antibodies binding to PSCA have also been utilized to modify nanodelivery systems. 109 , 110

While PSMA is the most extensively validated targeting moiety for prostate cancer nanomedicine, its clinical utility is significantly constrained by substantial heterogeneity in expression across patients, lesions, and disease stages. PSMA-negative cases (membranous staining ≤20%) have been identified in 15.0% of hormone-sensitive prostate cancer and 36.8% of mCRPC, indicating that more than one-third of CRPC patients may derive limited benefit from PSMA-targeted therapies. 111 Furthermore, dynamic expression changes have been observed between matched primary and metastatic samples. Beyond inter-patient variability, intra-tumoral heterogeneity poses an additional challenge, with 67.7% of primary lesions and 30.1% of bone metastases showing high variability in PSMA staining intensity within individual tumors. This finding suggests that PSMA-low or -negative subpopulations may evade therapy and serve as a reservoir for resistance, while significantly lower membranous PSMA expression in bone metastases (p < 0.001) indicates that the predominant metastatic site may be less amenable to PSMA targeting. 111 The molecular mechanisms underlying this heterogeneity are intricate, involving a transcriptional network with enhancer elements and differentially methylated regions. 112 In AR-negative advanced cancers, PSMA expression is frequently suppressed, and it is significantly correlated with AR expression levels (p < 0.001). This suggests that AR-targeted therapies may modulate PSMA expression and affect treatment sequencing. 111 In the context of PSMA-negative cases, which are particularly prevalent in mCRPC, alternative targets, including B7H3, STEAP1, and TROP2, have emerged as promising candidates. These findings, related to heterogeneity, directly impact the clinical applications of PSMA-targeted nanomedicines. 111 Patient selection via PSMA-PET or biopsy-based assessment is imperative. Serial rather than single-baseline monitoring is necessary due to dynamic expression changes. Combination strategies targeting both PSMA-positive and -negative cells may be required. Bone microenvironment-specific challenges necessitate additional bone-targeting or enhanced permeability strategies. The identification of alternative targets provides a framework for the development of second-generation nanoplatforms for PSMA-negative or therapy-progressed patients.

The use of tumor microenvironment-responsive nanoparticles enables precise, controlled release of therapeutic agents at the site of the lesion, thereby enhancing the therapeutic index. 113 , 114 Common designs include pH-sensitive, enzyme-sensitive, and redox-sensitive release. 113 , 114 The prostate cancer microenvironment is typically weakly acidic (pH 6.5–6.8), while the pH inside lysosomes/endosomes is even lower (pH 5.0–5.5). Based on these findings, it is possible to prepare nanoparticles containing acid-cleavable chemical bonds (eg, hydrazone bonds or acetal bonds) or pH-sensitive polymers (eg, polyhistidine or dimethylaminoethyl methacrylate). In an acidic environment, these nanoparticles undergo structural dissociation or a hydrophilic-to-hydrophobic transition, thereby accelerating drug release. 113 , 115 Prostate cancer tissues have been found to exhibit elevated levels of certain proteases, including matrix metalloproteinases (MMPs) such as MMP-2 and MMP-9, as well as cathepsin B. The use of substrate peptides from these enzymes serves as a linker, thereby facilitating the attachment of drugs or PEG shells to the nanocarriers. Following this connection, the linker is cleaved by the enzymes, thereby exposing the targeting ligand or releasing the drug. 113 , 116 The intracellular concentration of glutathione (GSH) in tumor cells (2–10 mM) is significantly higher than the extracellular concentration (2–20 μM). Disulfide-based nanocarriers can cleave in the reducing intracellular environment, thereby facilitating rapid drug release into the cytoplasm ( Figure 2 ). 113 , 117 Figure 2 Schematic illustration of nanoparticle-mediated targeted drug delivery in prostate cancer. Nanoparticles accumulate via passive targeting (enhanced permeability and retention, EPR effect) through leaky tumor vasculature. Active targeting is achieved by surface modification with PSMA-specific ligands, leading to receptor-mediated endocytosis. Once internalized, nanoparticles are trafficked through endosomes. The bottom panel shows tumor microenvironment-triggered drug-release mechanisms: low pH (acidic) triggers cleavage of hydrazone or acetal bonds, releasing the payload in the acidic endosomal/lysosomal compartment (pH 5.0–5.5) or tumor interstitium (pH 6.5–6.8). High GSH (intracellular) reduces disulfide bonds, releasing drug in the reducing intracellular environment (GSH concentration 2–10 mM vs 2–20 μM extracellular). MMP-2/9 overexpression cleaves peptide linkers, releasing drug in the tumor microenvironment where MMPs are elevated. These mechanisms improve therapeutic efficacy by ensuring site-specific drug liberation. The diagram illustrates nanoparticle-mediated targeted drug delivery in prostate cancer. Passive targeting is depicted with nanoparticles accumulating via the EPR effect, characterized by increased permeability and impaired lymphatic drainage. Active targeting involves surface modification with PSMA-specific ligands, leading to receptor-mediated endocytosis. The microenvironment of prostate cancer is shown with mechanisms for drug release: low pH triggers cleavage of hydrazone or acetal bonds, high GSH reduces disulfide bonds and MMP-2/9 cleaves peptide linkers. Nanoparticles release drugs like docetaxel and siRNA. Labels include ′Passive targeting′, ′Active targeting′, ′Microenvironment of Prostate Cancer′, ′Low pH′, ′High GSH′, ′MMP-2/9′, ′Drug release′, ′Nanoparticles′, ′Docetaxel′ and ′siRNA′. Diagram of nanoparticle-mediated drug delivery in prostate cancer, showing passive and active targeting mechanisms. Abbreviations : PSMA, prostate-specific membrane antigen; EPR, enhanced permeability and retention; GSH, glutathione; MMP, matrix metalloproteinase.

Nanostrategies to Overcome Drug Resistance

The development of chemotherapeutic agent resistance, as evidenced by the ineffectiveness of drugs such as docetaxel and cabazitaxel, constitutes a primary factor contributing to the failure of treatment regimens in patients diagnosed with CRPC. 118 The mechanisms of drug resistance involve multiple factors, including overexpression of drug efflux pumps (eg, P-glycoprotein [P-gp]), inactivation of apoptotic pathways, acquisition of tumor stem cell characteristics, and protective effects of the tumor microenvironment. 119–121 The potential of nanotechnology to circumvent or delay the emergence of drug resistance at multiple levels is of considerable interest.

Firstly, it has been demonstrated that nanoparticles can circumvent P-gp-mediated efflux mechanisms. Conversely, traditional small-molecule drugs are readily identified by P-gp and subsequently expelled from the cell following internalization. In contrast, nanoparticles enter cells through endocytosis. Once the drug is released intracellularly, efflux may be reduced due to spatial isolation from P-gp substrates, given their distribution (eg, lysosomes/cytoplasm). 122 Furthermore, co-encapsulating P-gp inhibitors (eg, verapamil, cyclosporine A, or zosuquidar) with chemotherapeutic agents in a single nanoparticle enables localized delivery of resistance-reversing agents, thereby reducing systemic toxicity. 123 , 124 For instance, PLGA nanoparticles co-loaded with docetaxel and verapamil have been shown to enhance docetaxel intracellular accumulation in cancer cells and restore its antineoplastic properties. 123

Secondly, nanocarriers can concurrently deliver two or more drugs, thereby producing synergistic effects. These nanocarriers can attack tumor cells through different mechanisms and reduce the risk of resistance to a single drug. 80 , 125 , 126 For instance, liposomes co-delivering docetaxel and resveratrol have been shown to enhance antitumor effects by promoting apoptosis. 127 Several studies have investigated the use of combination therapy, in which chemotherapeutic agents are co-delivered with siRNAs to silence genes associated with resistance. 128–130 For instance, a novel RGD-PEG-DSPE/CaP nanoparticle that carried both GRP78 siRNA and docetaxel effectively reversed resistance in prostate cancer cells in a drug-resistant CRPC model and significantly inhibited tumor growth. 128

Gene Therapy and RNA Delivery

The application of gene therapy in prostate cancer primarily focuses on silencing oncogenes, repairing tumor suppressor genes, and inducing immune responses. 131 However, naked nucleic acids are susceptible to rapid degradation by nucleases within an intact organism and, due to their negative charge, exhibit limited ability to traverse cell membranes. The ability of nanocarriers to protect nucleic acids and facilitate their efficient delivery is well-documented.

In CRPC, persistent activation of the AR and its splicing variants (such as AR-V7) is a key factor in ADT resistance. 132 Delivery of siRNAs targeting AR or AR-V7 has been shown to achieve specific silencing. For instance, encapsulating AR siRNA in LNPs has been shown to reduce AR protein expression and inhibit tumor growth in prostate cancer models. 133 It has been demonstrated in a variety of studies that the concurrent administration of PTEN messenger RNA (mPTEN) and AR siRNA (siAR) via LNPs restores PTEN and silences AR, thereby yielding synergistic therapeutic effects in prostate cancer cells. 134 Furthermore, investigations have examined the potential of siRNAs or shRNAs to target other relevant genes, including enhancer of zeste homolog 2 (EZH2), polo like kinase 1 (PLK1), and MYC. 135–137

The CRISPR/Cas9 gene editing system has the capacity to achieve curative treatment by either knocking out or repairing oncogenes. 138 Nonetheless, the molecular composition of CRISPR components (Cas9 mRNA or protein, sgRNA) is characterized by substantial molecular weights and concomitant delivery inefficiency. Nanotechnology offers a potential solution to this challenge. The delivery of CRISPR components to prostate cancer cells can be achieved by forming nanocomposites with cationic liposomes or polymers, or by physically adsorbing or chemically conjugating them to gold or mesoporous silica nanoparticles. 139–141 For instance, the delivery of CRISPR/Cas9 plasmids targeting the PLK1 gene using aptamer-liposome chimeras has been shown to result in significant gene silencing and tumor growth inhibition in both in vitro and in vivo settings. 139 A recent study identified DNA polymerase delta subunit 4 (POLD4) as a novel target for radiosensitization in prostate cancer and developed the liposome PIO@Lipo, which co-loads CRISPR-Cas9 plasmids with iron oxide nanoparticles. The system under discussion has been shown to synergize with radiotherapy, inducing extensive DNA damage, promoting tumor cell apoptosis, and remodeling the immunosuppressive microenvironment. 141

mRNA vaccines have been demonstrated to induce specific antitumor immunity by encoding tumor-associated antigens. 142 The use of nanocarriers, including lipoplexes, lipid nanoparticles, and polymeric nanoparticles, has been demonstrated to protect mRNA from degradation, thereby facilitating its uptake and translation by antigen-presenting cells. 143 In preclinical models of prostate cancer, PSMA mRNA-lipid nanoparticle vaccines have been shown to elicit robust CD8 + T-cell responses and retard tumor progression. 144

Immunonanotherapy

The overall response rate of immunotherapy in prostate cancer is low, primarily due to the immunosuppressive nature of the tumor microenvironment. This microenvironment is characterized by increased infiltration of regulatory T cells (Tregs), accumulation of myeloid-derived suppressor cells (MDSCs), and elevated levels of inhibitory cytokines, including transforming growth factor-β (TGF-β). 145 The potential of nanotechnology to enhance antitumor immunity hinges on its ability to modulate the immune microenvironment or to deliver immunomodulators.

Nanovaccines are a critical component of immunological nanotherapy. The encapsulation of tumor antigens and immunological adjuvants within nanoparticles, such as PLGA or liposomes, has been demonstrated to promote antigen uptake, maturation, and cross-presentation by dendritic cells (DCs). 146 In addressing the limitations of low immunogenicity and strong immunosuppression in “cold tumors” associated with prostate cancer, recent advancements in nanovaccine strategies have shifted away from reliance on pre-prepared antigens. Instead, they directly induce immunogenic cell death (ICD) at the tumor site using methods such as ultrasound and nanocarriers. This process releases tumor antigens in situ and simultaneously activates both innate and adaptive immune responses. Representative platforms include ultrasound-activated SATNAV nanoparticles, which integrate NRP-2 targeting, STING agonist delivery, and phase-change cavitation-mediated physical ablation, achieving a tumor suppression rate of 95.41%. 147 Aptamer-engineered liposomes (Apt-Flt3L@Lipo) have been shown to induce ICD and to recruit and activate key cDC1 dendritic cells in response to ultrasound stimulation. 148 The study investigates the synergistic effects of dendritic cell-derived extracellular vesicle vaccines (XCL1-DEVs) in combination with cisplatin chemotherapy. The hypothesis is that XCL1-DEVs enhance cross-presentation of anti-s and remodel the immune microenvironment. 149 Furthermore, epigenetically regulated NICER nanovesicles have been shown to significantly suppress postoperative recurrence and metastasis by inhibiting antigen degradation and integrating tumor stem cell antigens. 150 These strategies have demonstrated preclinical potential to convert “cold” tumors into “hot” tumors and to control primary and metastatic lesions effectively.

Modulating tumor-associated macrophages (TAMs) is another key strategy. The present state of immunonano-therapies targeting prostate cancer TAMs has undergone a transition from simple elimination strategies toward precise functional reprogramming and cellular engineering. From a pharmacological perspective, the IL-8/CXCR2 pathway is a crucial component of the CD47-SIRPα immune evasion signaling axis, which is pivotal in restoring the phagocytic function of macrophages. 151 Concurrently, delivery systems such as gold nanoparticles, CSF-1R siRNA, or STING agonists can re-educate pro-tumor M2-type TAMs into anti-tumor M1-type TAMs. 152–154 STING agonists have been shown to demonstrate significant synergistic effects when combined with ADT. 154 With respect to carrier innovation, bacterial outer membrane vesicles and macrophage membrane-coated nanoparticles have demonstrated high efficiency in targeting and disrupting immune evasion. 155 , 156 In the domain of cell engineering, the in situ delivery of CAR genes via nanocarriers directly converts in vivo TAMs into “ready-to-use” CAR-M cells, thereby promoting the inflammatory transformation of tumors. 157 Furthermore, the introduction of the CD86 co-stimulatory molecule through arming modification further enhances their M1 polarization capacity and T-cell activation function, demonstrating strong synergistic potential when combined with PD-L1 inhibitors. 158 Furthermore, hyaluronic acid-functionalized dual-targeted nanocarriers enable simultaneous, precise targeting of both tumor cells and TAMs, marking a new phase in TAM-targeted nanotherapy characterized by multidimensional synergy and precise regulation. 159

Integrated Diagnostic and Therapeutic Nanoplatform

An integrated diagnosis-and-therapy nanoplatform is a single nanoparticle that simultaneously integrates diagnostic (imaging) and therapeutic functions, enabling concurrent tumor detection, treatment monitoring, and evaluation of therapeutic efficacy. Engineered cell membranes refer to plasma membranes isolated from specific cell types (eg, cancer cells, immune cells, erythrocytes) and coated onto nanoparticle surfaces to confer biological functionalities. 160 This “camouflage” strategy enables nanoparticles to evade immune recognition, prolong circulation time, and achieve homologous targeting. 161 Homologous targeting is the ability of cancer cell membrane-coated nanoparticles to preferentially adhere to and be internalized by cancer cells of the same origin. 162 Additionally, engineered cell membranes can be genetically modified or chemically functionalized to display targeting ligands, immune checkpoint inhibitors, or other therapeutic moieties, creating multifunctional “smart” nanoplatforms with enhanced biocompatibility and targeting precision. 163 Integrated diagnostic and therapeutic platforms, based on multifunctional nanocarriers, employ core targets (PSMA, PSCA, AR, folate receptor alpha [FRα], and CD44, etc) to achieve active tumor targeting. 164 This is achieved through surface modification with PSMA ligands, folic acid, hyaluronic acid, or engineered cell membranes, thereby enhancing the accumulation of drugs or probes at the tumor site. 164–168 About imaging modalities, these platforms integrate a variety of techniques, including MRI, near-infrared II (NIR-II) fluorescence, and other related methods. For instance, SPIONs are used for MRI imaging, 169 proprietary dyes (such as 2TT-oC26B) are employed for NIR-II fluorescence imaging, 170 and multifunctional probes are developed to enable multimodal imaging that combines fluorescence and photoacoustic techniques, thereby providing a more comprehensive visualization of tumors. 171 In the therapeutic dimension, this platform serves as a delivery vehicle for chemotherapeutic agents, including docetaxel. 166 Additionally, it integrates photothermal and photodynamic therapies to achieve highly efficient tumor ablation. 172 Furthermore, the incorporation of PROTAC technology facilitates the selective degradation of specific proteins, while ferroptosis inducers are employed to circumvent drug resistance. Additionally, the delivery of siRNAs for gene silencing is enabled in conjunction with a controlled drug-release mechanism that mitigates systemic toxicity. 167 , 168 , 173 In addition, ultrasound-mediated therapy has been incorporated into the integrated diagnosis and treatment design. The proposed methodology involves creating targeted nanobubbles to enhance ultrasound contrast and subsequently destroying tumors via physical effects and cellular autophagy in response to ultrasound irradiation. 171 Concurrently, smart nanosystems that are responsive to tumor microenvironment characteristics (such as specific enzymes, acidic pH, or high GSH concentrations) or external physical stimuli (such as near-infrared light or ultrasound) can achieve “site-specific activation” of imaging or drug release. This further enhances the precision of diagnosis and treatment ( Figure 3 ). 167 , 171 In sum, integrated nanoplatforms for the diagnosis and treatment of prostate cancer are evolving rapidly toward multifunctional integration, intelligent responsiveness, and precise targeting. These platforms are expected to provide breakthrough solutions for the early diagnosis and personalized treatment of prostate cancer ( Table 1 ). 174 Figure 3 This theranostic nanoplatform integrates diagnosis, therapy, and real-time response monitoring. The core-shell nanoparticle (eg, SPION@MSN) carries multiple functional modules. Imaging modules: The SPION core is used for MRI, while the NIR-II fluorescent dye is used for fluorescence imaging. Photoacoustic agents are used for photoacoustic imaging. Therapeutic modules: Chemotherapeutic payload (docetaxel); PROTAC molecules targeting AR/AR-V7; siRNA for gene silencing; ferroptosis inducers. Responsive linkages: pH-sensitive hydrazone bonds, GSH-reducible disulfide bonds, and MMP-cleavable peptide linkers. PSMA-mediated targeting enhances uptake via receptor-mediated endocytosis. The lower timeline illustrates the closed-loop “diagnosis (pre-treatment imaging) — therapy (drug release, combination treatment) — assessment (post-treatment imaging, response monitoring)” cycle, enabling personalized treatment adaptation. A diagram shows a theranostic feedback loop with SPION@MSN-PSMA, comprising Diagnosis, Treatment, Targeted and Response. Diagnosis uses SPION core for MRI, NIR-II fluorescence and photoacoustic imaging. Treatment includes docetaxel, PROTAC molecules targeting AR/AR-V7 and siRNA for gene silencing. Targeted features PSMA targeting and biomimetic cell membrane coating. Response involves pH-sensitive hydrazone bonds, GSH-reducible disulfide bonds and MMP-cleavable peptide linkers. The loop operates in three stages: After injection, nanoparticles target PSMA positive cells, leading to endocytosis into lysosomes; Response Release, where low pH/high GSH causes structural disintegration, releasing drugs/siRNA/PROTACs into the cytoplasm; and Imaging Feedback, involving MRI/NIR-II signal changes and real-time treatment efficacy evaluation. Diagram of a theranostic feedback loop with diagnosis, treatment, targeted and response components. Abbreviations : SPION, superparamagnetic iron oxide nanoparticle; MSN, mesoporous silica nanoparticle; MRI, magnetic resonance imaging; NIR-II, second near-infrared window; PROTAC, proteolysis-targeting chimera; AR, androgen receptor; siRNA, small interfering RNA; GSH, glutathione; MMP, matrix metalloproteinase; PSMA, prostate-specific membrane antigen. Table 1 Representative Nanocarrier Systems for Prostate Cancer Therapy Nanocarrier Type Representative Material/Structure Payload/Active Molecule Targeting Strategy Main Features and Model Key Effect Reference Liposome PEGylated liposome; anti-PSMA antibody-conjugated liposome Doxorubicin; docetaxel; siRNA; genistein; plumbagin Passive (EPR) or active (PSMA, folate) Prolonged circulation; reduced cardiotoxicity; CRPC models; LNCaP/PC-3 xenografts Higher tumor inhibition in PSMA⁺ xenografts; reduced cardiotoxicity vs free drug; IC 5 0 reduced by ~40% in combination therapy [ 78–80 , 126 , 127 ] Polymeric nanoparticle PLGA; PAMAM dendrimer Docetaxel; cabazitaxel; camptothecin PSMA ligand (DUPA, A10 aptamer); folate Controlled release; biodegradable; PSMA-positive xenografts; enhanced intracellular uptake Increased intracellular uptake (2.5-fold vs non-targeted in LNCaP, 72 h); lower IC 5 0 (0.8 μM vs 3.2 μM for free docetaxel, 48 h) [ 81 , 85 , 108 ] Inorganic nanoparticle Gold nanoshell/rod (AuroShell ® ); mesoporous silica (MSN); Fe 3 O 4 (SPION) Photothermal agent; photosensitizer; chemotherapeutics; MRI contrast EPR or active (PSMA, folate, hyaluronic acid) Photothermal/photodynamic/magnetic hyperthermia; focal ablation; theranostic integration Complete tumor regression in PC-3 xenografts with AuroShell ® photothermal therapy (i.v. injection, 24 h accumulation, 800 nm NIR laser 4 W/cm 2 × 3 min) [ 86–92 ] Lipid nanoparticle (LNP) Cationic liposome; ionizable lipid nanoparticle AR siRNA; PTEN mRNA; CRISPR/Cas9; AR-V7 siRNA Passive or ligand-modified (PSMA aptamer, folate) Gene silencing/editing; endosomal escape; CRPC models; LNCaP xenografts Reduced AR protein expression (70% knockdown by Western blot); tumor growth inhibition (70%) in LNCaP xenografts (i.v., 0.5 mg/kg siRNA, twice weekly × 3 weeks) [ 133 , 134 , 139 , 141 ] Nanovaccine/immune nanoparticle PLGA; liposome; bacterial outer membrane vesicle (OMV); cell membrane-coated nanoparticle Tumor antigen; STING agonist; Flt3L; TLR agonists Passive or DC targeting (DEC-205, CD11c); intratumoral injection Induces ICD; reverses immunosuppressive TME; converts “cold” to “hot” tumors; RM-1 prostate cancer model Enhanced CD8⁺ T cell response (4-fold increase in splenic CD8⁺ T cells); tumor inhibition rate >95% in RM-1 model (intratumoral, 3 doses at 7-day intervals) [ 147–150 , 154 ] Theranostic nanoplatform SPION@MSN; quantum dot-drug conjugate; gold nanorod-PROTAC MRI/NIR-II/PA probe + docetaxel; PROTAC; ferroptosis inducer; siRNA PSMA; pH/GSH/MMP responsive; cell membrane coating Simultaneous diagnosis and therapy; real-time monitoring; closed-loop “diagnosis-treatment-assessment” Preoperative staging + intraoperative guidance + response assessment in PC-3 xenografts (i.v., MRI T2-weighted at 3T, NIR-II with 808 nm excitation, + PTT) [ 165 , 167 , 169–171 , 173 ] Abbreviations : AR, androgen receptor; CRPC, castration-resistant prostate cancer; DC, dendritic cell; EPR, enhanced permeability and retention; GSH, glutathione; IC 5 0 , half-maximal inhibitory concentration; ICD, immunogenic cell death; LNP, lipid nanoparticle; MMP, matrix metalloproteinase; MRI, magnetic resonance imaging; MSN, mesoporous silica nanoparticle; NIR, near-infrared; NIR-II, second near-infrared; OMV, outer membrane vesicle; PAMAM, polyamidoamine; PEG, polyethylene glycol; PLGA, poly(lactic-co-glycolic acid); PROTAC, proteolysis-targeting chimera; PSMA, prostate-specific membrane antigen; PTT, photothermal therapy; ROS, reactive oxygen species; siRNA, small interfering RNA; SPION, superparamagnetic iron oxide nanoparticle; STING, stimulator of interferon genes; TME, tumor microenvironment.

Current Status and Challenges of Clinical Translation

Nanomedicines Currently in Clinical Trials

While a considerable number of nanotechnology applications for prostate cancer remain in the preclinical stage, some nanomedicines have already entered clinical trials. The termination of several of these trials was attributed to the failure to meet stipulated efficacy expectations. Conversely, other trials have demonstrated encouraging progress in diagnostic applications.

In the domain of targeted chemotherapy, BIND-014 is a polymeric nanoparticle that targets PSMA, is PEG-modified, and is loaded with docetaxel. Preclinical studies have demonstrated that it can significantly enhance docetaxel accumulation at the tumor site, thereby improving antitumor activity and tolerability. 175 In the initial Phase I trial, which included 55 patients with advanced solid tumors, the drug demonstrated dose-linear pharmacokinetics and an extended circulation half-life, with adequate overall tolerability and no unexpected toxicities. In the overall population, one complete response and five partial responses were observed, with responses occurring in patients with prostate cancer regardless of PSMA expression status. 176 A subsequent Phase II trial (60 mg/m 2 every 21 days in combination with prednisone) in chemotherapy-naïve patients with mCRPC who had progressed on abiraterone and/or enzalutamide demonstrated a PSA response rate of 30% (12/40) among 40 patients. With an objective response rate of 32% (6/19) in 19 patients with measurable lesions, a median imaging progression-free survival of 9.9 months, and 50% (13/26) of patients achieving CTC conversion, based on non-EPCAM-dependent platform detection, baseline PSMA-positive CTCs were preferentially reduced after treatment, and antitumor activity may be correlated with CTC PSMA expression levels. The present findings suggest that this nanomedicine demonstrates clinical activity and manageable safety in mCRPC and has the potential to identify patients who may benefit through CTC PSMA-based stratification. 177 Despite these modest signals of activity, the agent was not advanced to Phase III and ultimately failed to obtain regulatory approval. Several factors likely contributed to this outcome. First, the reliability of PSMA expression for targeting may have been compromised by significant inter-patient and intra-tumoral heterogeneity, with approximately 15–37% of CRPC cases exhibiting low or absent PSMA membranous staining. 111 Second, the heterogeneous EPR effect in human tumors—which is considerably less pronounced than in murine xenografts—likely resulted in suboptimal nanoparticle accumulation at metastatic sites, particularly in bone lesions where the dense matrix and elevated interstitial pressure impede extravasation. 178 Third, the trial design may have been limited by the lack of biomarker-driven patient selection. Although baseline PSMA-positive CTCs were preferentially reduced after treatment, and antitumor activity appeared correlated with CTC PSMA expression levels, this stratification was not used for enrollment. 177 Collectively, these observations underscore the importance of: (a) validating target expression in metastatic lesions before treatment, (b) incorporating patient selection biomarkers into trial design, and (c) recognizing that active targeting cannot fully compensate for inadequate passive accumulation when the EPR effect is heterogeneous.

CRLX101, another nanomedicine, is a camptothecin-nanomedicine conjugate based on a cyclodextrin-polyethylene glycol polymer. The original design of the study was to reverse acquired resistance to enzalutamide by downregulating HIF-1α. Preclinical studies confirmed the synergistic antitumor activity of the combination of enzalutamide and the other drug. 179 However, the Phase II trial ( NCT03531827 ) that was evaluating the combination of the drug with enzalutamide in patients with mCRPC who had progressed after enzalutamide treatment was terminated due to dose-limiting toxicity. 180 A Phase IV study of nanoliposomal docetaxel (NDLS) was conducted in India and reported the following outcomes: an overall objective response rate of 16.9%, a disease control rate of 44.2%, and a median progression-free survival of 12 months. 181

In the context of localized ablation therapy, the AuroLase ® therapy employs PEG-coated silicon-gold core-shell nanoparticles (AuroShell ® Particles, with a hydrodynamic diameter of approximately 150 nm). On the first day, patients receive a systemic infusion of the nanoparticles. On the second day, sub-ablative near-infrared laser irradiation is applied to the lesion area via a perineal approach under MRI-ultrasound fusion guidance. The nanoparticles efficiently convert light energy into thermal energy, effectively destroying the tumor while sparing surrounding normal tissue. 182 , 183 In the cohort of 101 patients diagnosed with localized prostate cancer (Gleason score 1–3) who completed the treatment regimen, a 1-year targeted biopsy negativity rate of 68% was observed (95% confidence interval [CI], 58–77%), with a notable decrease in mean PSA level from 8.3 ng/mL at baseline (95% CI, 7.6–9.1) to 4.3 ng/mL (95% CI, 3.5–5.1). It is important to note that among the 5 patients who did not complete the full course of treatment, 3 cases were due to adverse reactions during infusion, and 2 cases were due to equipment unavailability. In addition, no substantial alterations in patients’ urinary or sexual function were observed at the 1-year mark compared with baseline. 182 With respect to safety, no serious adverse events related to systemic infusion of the nanoparticle system occurred during the 2-day treatment period (all adverse events were CTCAE grade ≤2). Additionally, no MRI artifacts or abnormal effects on the liver or spleen were observed. 182 This clinical experience yielded several key lessons. First, patient selection is paramount: treatment success was significantly associated with maximum lesion diameter on MRI (P = 0.046), suggesting that smaller, well-defined lesions are more amenable to focal ablation. Second, the favorable safety profile of gold nanoshells supports the feasibility of nanoparticle-based focal therapy. However, long-term follow-up data on nanoparticle biodistribution and clearance remain limited. Third, the 68–73% success rate, while encouraging for a minimally invasive approach, indicates that approximately one-third of patients may require additional or alternative therapy, highlighting the need for improved patient stratification and potentially combination with other modalities. Fourth, the technology’s application is currently limited to low- and intermediate-risk localized disease; its utility in higher-risk or metastatic settings remains to be established. 184

The following nanotechnologies are currently entering clinical practice: In diagnostic imaging, ferumoxtran, an MRI contrast agent derived from iron oxide nanoparticles, has met its primary objective in a multicenter study. This study validated the enhanced sensitivity and negative predictive value (NPV) of ferumoxtran for detecting lymph node metastases in patients with prostate cancer, surpassing the performance of multidetector CT (MDCT). 185 Concurrently, a clinical trial ( NCT04167969 ) is ongoing to assess the safety and efficacy of a PSMA-targeted ultrafine silicon nanoparticle tracer ( 64 Cu-NOTA-PSMAi-PEG-Cy5.5-C’ dots) for intraoperative detection of prostate cancer cells. This trial aims to evaluate its potential for preoperative PET/MRI localization and intraoperative fluorescence navigation. The application of nanotechnology in prostate cancer drug therapy is also evident in novel explorations of tumor immunotherapy. 186 Mobilan (M-VM3) is a recombinant non-replicating adenovirus immunotherapy drug in nanoparticle form. The Phase Ib clinical trial of Mobilan in prostate cancer patients is a multicenter, randomized, double-blind, placebo-controlled study ( NCT02844699 ) evaluating the safety, pharmacodynamics, and preliminary efficacy of different injection regimens following direct injection into the prostate as neoadjuvant therapy. 187 The results have not yet been published in the scholarly literature ( Table 2 ). Table 2 Summary of Representative Nanotechnologies in Clinical Trials for Prostate Cancer Nanotechnology Platform Type Target/Mechanism Payload/Function Study Design Primary Endpoint Key Safety Results Key Outcomes and Current Status Final Conclusion and Key Reason Clinical Trial ID Reference BIND-014 PSMA-targeted PEGylated polymeric nanoparticle PSMA active targeting Docetaxel Phase II, single-arm PSA response rate (≥50% decline) Well tolerated; no unexpected toxicities; Grade 3–4 AEs in 22%; no dose-limiting toxicity PSA RR 30% (12/40); ORR 32% (6/19); median rPFS 9.9 months; 50% CTC conversion; Completed, not approved Failed to advance: Insufficient efficacy; lack of biomarker-driven patient selection; heterogeneous EPR and PSMA expression in bone metastases NCT01300533 [ 175–177 ] CRLX101 (NLG207) Cyclodextrin-PEG polymer-drug conjugate HIF-1α inhibition (reverses enzalutamide resistance) Camptothecin (topoisomerase I inhibitor) Phase II, open-label, combination with enzalutamide Safety and efficacy (PSA response, radiographic PFS) Dose-limiting toxicity observed; combination regimen not tolerated at planned doses Study terminated early; Terminated Terminated due to dose-limiting toxicity: Favorable preclinical synergy did not translate to clinical tolerability; therapeutic window narrower than anticipated NCT03531827 [ 179 , 180 ] AuroLase ® PEGylated silica-gold core-shell nanoshell (AuroShell ® ) Photothermal ablation (NIR laser activation) None (physical ablation via heat generation) Prospective, open-label, single-arm, multicenter 1-year negative MR/US fusion targeted biopsy No severe AEs (all CTCAE grade ≤2); no MRI artifacts; 3 infusion-related reactions requiring discontinuation (3%) 68% negative biopsy at 1 year (95% CI: 58–77%); mean PSA 8.3→4.3 ng/mL; preserved urinary/sexual function; Completed, not yet FDA approved Partial success, defined scope: Promising focal therapy for low/intermediate-risk PCa; limited to specific niche; requires specialized equipment; ~1/3 patients need additional therapy NCT02680535 [ 87 , 88 , 182 , 183 ] Ferumoxtran-10 Ultrasmall superparamagnetic iron oxide nanoparticle (USPIO) MRI contrast agent (lymph node metastasis detection) None (imaging agent) Prospective, multi-cohort, diagnostic Sensitivity and negative predictive value (NPV) vs multidetector CT (MDCT) Good safety profile; no major adverse events reported; rare hypersensitivity reactions Met primary endpoint; sensitivity superior to MDCT; NPV improved; Approved in some regions (EU); limited adoption Diagnostic success, limited uptake: Replaced by PSMA-PET/CT in many centers; logistical challenges; reimbursement limitations NCT02112266 [ 185 ] 64 Cu-NOTA-PSMAi-PEG-Cy5.5-C’ dots Ultrasmall silica nanoparticle (C’ dot) PSMA-targeted PET/MRI and NIRF intraoperative guidance 64 Cu radionuclide + Cy5.5 NIRF dye Phase I, open-label, intraoperative navigation Safety and feasibility; PET/MRI imaging quality; fluorescence signal detection Not yet reported (ongoing); safety monitoring in progress Preliminary imaging data promising; Ongoing Not yet evaluable: Phase I safety/feasibility study; intraoperative guidance potential to be confirmed NCT04167969 [ 186 ] Mobilan (M-VM3) Recombinant non-replicative adenoviral nanoparticle TLR5 agonist/immune activation Encodes TLR5 ligand (flagellin) for innate immune activation Phase Ib, randomized, double-blind, placebo-controlled, neoadjuvant Safety (AEs, DLT); pharmacodynamics (immune cell infiltration, cytokine response) Not yet reported (ongoing); monitoring for immune-related AEs Immunological endpoints under evaluation; Ongoing Not yet evaluable: Phase Ib pharmacodynamics study; efficacy and optimal dosing to be determined NCT02844699 [ 187 ] Nanosomal docetaxel lipid suspension (NDLS) Liposomal docetaxel (nanosomal formulation) Passive targeting (EPR) Docetaxel Phase IV, multicenter, open-label (India) Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) Acceptable safety profile; AEs consistent with docetaxel; no unexpected toxicities ORR 16.9%; DCR 44.2%; median PFS 12 months; Approved in India Approved in India: Acceptable efficacy and safety in real-world setting; regulatory approval obtained in India but not widely adopted internationally CTRI/2018/02/012212 [ 181 ] Abbreviations : AE, adverse event; CI, confidence interval; CRPC, castration-resistant prostate cancer; CTC, circulating tumor cell; CTCAE, Common Terminology Criteria for Adverse Events; DCR, disease control rate; DLT, dose-limiting toxicity; EPR, enhanced permeability and retention; HIF-1α, hypoxia-inducible factor-1α; MDCT, multi-detector computed tomography; mCRPC, metastatic castration-resistant prostate cancer; MRI, magnetic resonance imaging; NDLS, nanosomal docetaxel lipid suspension; NIRF, near-infrared fluorescence; NPV, negative predictive value; ORR, objective response rate; PCa, prostate cancer; PEG, polyethylene glycol; PFS, progression-free survival; PSMA, prostate-specific membrane antigen; RR, response rate; rPFS, radiographic progression-free survival; TLR5, Toll-like receptor 5; USPIO, ultrasmall superparamagnetic iron oxide nanoparticle.

The clinical translation of prostate cancer nanomedicines has yielded instructive lessons across several representative platforms. BIND-014 did not advance beyond Phase II due to its insufficient efficacy (PSA response rate 30% vs 45–50% with standard docetaxel), lack of biomarker-driven patient selection despite a correlation between antitumor activity and CTC PSMA expression, heterogeneous EPR effect in human tumors (particularly in bone metastases with dense matrix and elevated interstitial pressure), and PSMA heterogeneity (15–37% of CRPC cases are PSMA-negative), underscoring that active targeting cannot compensate for inadequate passive accumulation and that patient stratification biomarkers are essential. The termination of CRLX101 in Phase II was attributed to the occurrence of dose-limiting toxicity, underscoring the notion that the presence of favorable preclinical synergy does not ensure clinical tolerability. This outcome emphasizes the necessity for meticulous dose optimization in combination regimens, with careful consideration for nanoparticle pharmacokinetics to ensure safe and effective clinical outcomes. AuroLase ® demonstrated a 68% one-year negative biopsy rate and preserved functional outcomes, yet its application remains restricted to low/intermediate-risk localized disease, with approximately 33% necessitating additional therapy, 3% experiencing infusion-related reactions, and procedural complexity impeding widespread adoption. Ferumoxtran-10 demonstrated efficacy in achieving diagnostic success; however, its clinical uptake was constrained by several factors, including competition from PSMA-PET/CT, logistical challenges, reimbursement barriers, and concerns regarding long-term iron accumulation. This case underscores the notion that diagnostic superiority alone is insufficient for translating a test into clinical practice. Beyond these, 64 Cu-NOTA-PSMAi-PEG-Cy5.5-C’ dots and Mobilan both face challenges, including demonstrating added value over existing modalities, navigating regulatory processes for theranostic devices, and optimizing dosing and immunogenicity. Collectively, these experiences indicate that clinical success requires not only innovative nanomaterial design but also biomarker-driven patient selection, careful dose optimization, demonstration of clear advantage over existing alternatives, and navigation of complex regulatory and reimbursement pathways.

Major Challenges

Despite the strides made in nanotechnology, particularly in the treatment of prostate cancer, translating laboratory findings into clinical practice remains a multifaceted challenge. These challenges span multiple levels, including biological barriers, safety concerns, large-scale production challenges, and regulatory hurdles.

With respect to biological barriers, upon entering the human body, nanomedicines must sequentially overcome “multiple physiological barriers” from the vasculature to the cells. The vascular abnormalities, matrix compaction, and elevated interstitial fluid pressure that are characteristic of the prostate tumor microenvironment constitute physical barriers that hinder drug penetration into deep tumor tissue. 188 Furthermore, passive targeting based on the EPR effect exhibits significant heterogeneity across human tumors. In combination with the nanoparticle trapping facilitated by the dense matrix, this phenomenon leads to non-specific accumulation of the drug in vital organs such as the liver and spleen, resulting in suboptimal therapeutic efficacy. 189 Despite the potential of nanomedicines to reach tumor cells, they may become entrapped and degraded within endosomes or lysosomes. This could impede the effective intracellular delivery of therapeutic agents, thereby hindering the desired therapeutic outcomes. The issue is further complicated by prostate cancer cells’ ability to develop multidrug resistance through genetic mutations or the activation of compensatory pathways. This necessitates the use of nanodelivery systems to deliver drugs with multiple mechanisms of action synergistically, thereby further increasing the complexity of delivery design. 99

Safety considerations for prostate cancer nanotechnologies differ markedly by application type, requiring tailored approaches. For diagnostic probes such as imaging agents and nanosensors, administered in low, single doses, key concerns include chronic accumulation of inorganic nanoparticles in the reticuloendothelial system with incompletely characterized long-term fate, clearance kinetics that affect imaging windows, and immune responses including hypersensitivity and complement activation via protein corona formation. 190–192 For systemic therapeutic nanomedicines given repeatedly over months or years, risks include chronic accumulation of non-biodegradable carriers, long-term effects on sensitive organs, immunogenicity from protein corona formation and anti-PEG antibodies leading to accelerated clearance, off-target accumulation in liver and spleen causing hepatotoxicity or immunosuppression, and batch-to-batch consistency challenges where minor variations alter pharmacokinetics and toxicity. 193–195 Gene editing delivery systems present unique concerns including immunogenicity from nucleic acids and Cas9 protein triggering innate immune responses, off-target genome editing, and long-term risks such as oncogenesis from permanent genomic modifications. 196 , 197 Local ablation platforms, administered directly to the tumor, raise issues of local tissue damage from heat or reactive oxygen species if not precisely controlled, nanoparticle retention and potential redistribution, and stability requirements to maintain therapeutic properties. 198 , 199 These application-specific safety profiles must be systematically characterized to support clinical translation.

The transition from laboratory-scale synthesis to GMP-compliant industrial production represents a formidable barrier to nanomedicine clinical translation, with key challenges spanning physicochemical consistency, manufacturing technology selection, quality-by-design (QbD) implementation, and sterilization/storage stability. 200 While critical parameters such as nanoparticle size, surface charge, and drug loading can be meticulously controlled at small scale, maintaining batch-to-batch uniformity during industrial production remains technically challenging, as even minor physicochemical variations can significantly alter pharmacokinetics, efficacy, and toxicity. 100 , 189 Large-scale production employs methodologies including nanocrystallization, extrusion, supercritical fluid technology, and microfluidics—with emerging self-nanoemulsification achieving throughput up to 5 L/min—though each technique presents distinct scalability, cost, and reproducibility trade-offs. 201 QbD implementation is essential for ensuring consistency through systematic identification of critical quality attributes and process parameters, defining target product profiles, establishing design space, and developing control strategies. Nanomedicines pose unique terminal sterilization challenges, as conventional methods (heat, radiation, filtration) can alter nanoparticle properties or drug release profiles—particularly for lipid-based carriers—while long-term stability concerns including aggregation, drug leakage, and degradation necessitate approaches such as lyophilization, provided that reconstitution does not compromise nanoparticle integrity. 202

The crux of the issue lies in a fundamental dissonance between the prevailing evaluation and approval mechanisms and the intricate, pioneering nature of nanomedicines. For an extended period, the drug regulatory system has been predominantly focused on small-molecule chemical drugs or traditional biologics, which are characterized by single components, well-defined structures, and clear mechanisms of action. However, multifunctional, smart-responsive nanocomposite systems that integrate diagnosis and treatment are complex, multi-component assemblies with variable structures. A paucity of explicit guidelines on the definition, classification, and evaluation criteria for these entities characterizes the existing regulatory framework. This results in significant uncertainty and high costs associated with case-by-case communication across nonclinical studies and manufacturing quality control, as well as clinical trial design, which greatly delays the R&D process. 203 The regulatory landscape for nanomedicines is characterized by the absence of a dedicated pathway, with both the FDA and EMA applying existing frameworks on a case-by-case basis while incorporating nano-specific considerations. The FDA, which has no separate nanomedicine category, issued a 2022 Guidance for Industry on “Drug Products, Including Biological Products, that Contain Nanomaterials” that employs a risk-based framework emphasizing robust particle characterization (size, charge, morphology, surface chemistry), batch-to-batch reproducibility, nano-specific toxicology assessments (particularly immune activation and reticuloendothelial system uptake), and demonstration of sameness for generics—a particular challenge as minor physicochemical variations can significantly impact safety and efficacy. 203 , 204 The EMA has issued reflection papers and guidelines on nanomedicines, with a greater emphasis on risk prevention rather than purely technical assessments. The EMA’s risk assessment of nanoproducts encompasses four components: hazard identification, hazard characterization, exposure assessment, and risk characterization. 204 Global harmonization remains elusive, as regulatory variations across regions—with the FDA lacking a separate nanomedicine category, the EMA providing more detailed reflection papers, and Japan’s PMDA offering guidance with strong emphasis on chemistry, manufacturing, and control—pose significant challenges for manufacturers seeking to scale up production while maintaining compliance with diverse standards. 205

The economic viability of nanomedicines is a critical determinant of clinical adoption and reimbursement, with cost analyses revealing a complex trade-off between elevated manufacturing expenses and potential downstream healthcare savings. Comparative analyses of FDA-approved nanomedicines versus novel small molecular entities and biologics have demonstrated that the median cost of pivotal trials for nanomedicines is approximately 47% that of conventional agents approved in the same timeframe, suggesting that higher manufacturing and raw material costs may be partially offset by savings in clinical development—a finding that enhances translational viability. 206 Nevertheless, nanomedicine manufacturing necessitates specialized GMP-compliant infrastructure, high-purity raw materials, and rigorous quality control testing (including batch-release assays for size distribution, drug loading, and release kinetics), all of which contribute to increased cost of goods compared with traditional small-molecule drugs. However, the targeted delivery and reduced systemic toxicity of nanomedicines may lower overall healthcare expenditures by minimizing adverse event management, reducing hospitalizations, and potentially enabling outpatient administration. For prostate cancer specifically, the established precedent of expensive yet effective therapies—including novel hormonal agents (abiraterone, enzalutamide) and radiopharmaceuticals ( 223 Ra-dichloride, 177 Lu-PSMA-617)—suggests that payers and healthcare systems may accept higher upfront costs for nanomedicines that demonstrate superior efficacy, meaningful toxicity reduction, or the ability to overcome drug resistance in castration-resistant disease, provided that robust cost-effectiveness evidence (eg, quality-adjusted life-year gains) supports the value proposition. Generating such evidence remains methodologically challenging due to the complexity of modeling long-term outcomes and the lack of standardized health economic frameworks specific to nanomedicines. Yet, it is essential for securing reimbursement and market access across diverse healthcare systems.

The clinical success of nanomedicines critically depends on identifying patients most likely to benefit through emerging stratification strategies encompassing histopathological biomarkers, PSMA expression, CTC-based profiling, and tumor microenvironment markers. Histopathological quantification of macrophages and blood vessels can differentiate tumors with high versus low nanomedicine accumulation, while imaging-based EPR biomarkers and patient-derived organoid models recapitulating clinical heterogeneity support patient selection and biomarker validation. 207 Given that PSMA-negative cases comprise 15.0% of hormone-sensitive prostate cancer and 36.8% of mCRPC, patient selection based on PSMA-PET imaging or biopsy-based assessment (membranous staining >20%) is essential for PSMA-targeted nanomedicines. 111 The BIND-014 Phase II trial further demonstrated that baseline PSMA-positive CTCs were preferentially reduced after treatment and that antitumor activity correlated with CTC PSMA expression, suggesting CTC-based molecular profiling could identify likely responders. 177 For TME-responsive nanocarriers, functional biomarkers including cathepsin B levels and GSH/GSSG ratios—which correlate with patient-specific responses in organoid models—could guide selection. 208 Future clinical trial designs should incorporate pre-treatment biomarker assessment for patient enrichment, stratification by biomarker status, and adaptive designs enabling biomarker-driven treatment assignment, as identification of predictive biomarkers of nanomedicine accumulation is essential for effective patient stratification.

Future Prospects and Directions

Smart Nanosystems and Precise Spatiotemporal Control

To address the challenges posed by the low delivery efficiency and substantial side effects characteristic of conventional nanomedicines, the development of next-generation smart nanosystems has focused on two key aspects: precise targeting and controlled drug release. The objective of these efforts is to ensure the precise delivery of the correct dose of medication at the intended time and location. Utilizing PSMA as a “navigation beacon” and modifying the surface of nanocarriers with PSMA ligands or novel nanobodies enables precise recognition and accumulation of these carriers in tumor cells, thereby enhancing drug concentration at the lesion site while concomitantly reducing systemic side effects. 165 Concurrently, by capitalizing on the tumor microenvironment (eg, acidic pH, high GSH concentrations) or external physical stimuli (eg, light, ultrasound, magnetic fields), carriers can be engineered to “unlock” and release drugs locally within the tumor. For instance, pH-responsive mesoporous silica nanoparticles have been shown to trigger drug release in acidic environments. 209 At the same time, systems responsive to external magnetic fields have demonstrated the capability for “on-demand” drug delivery. 173 Furthermore, by integrating therapeutic functions—such as chemotherapy, photothermal therapy, and photodynamic therapy—with diagnostic capabilities—such as MRI and photoacoustic imaging—into a single platform, a diagnostic-therapeutic integrated nanotechnology platform can enable real-time monitoring of drug distribution and immediate assessment of treatment efficacy, thereby providing a basis for personalized treatment decisions. 165 , 173 , 209

Multimodal Synergistic Therapy and Remodeling of the Immune Microenvironment

Given the complexity of tumors, a single therapy is often insufficient for a cure. The prevailing future trend is the use of nanotechnology platforms for the organic integration of multiple therapeutic mechanisms, with particular emphasis on activating the body’s immune system to attack tumors. Conventional chemotherapy and radiotherapy have been shown to exert a direct effect on tumor cells, leading to their demise. However, a secondary effect of these treatments is the release of tumor antigens, which are proteins expressed by cancerous cells. This release of antigens, in turn, can stimulate an immune response in the body, a process known as ICD. In combination with immune checkpoint inhibitors or tumor vaccines, this approach has been shown to elicit synergistic antitumor immune responses. 125 Furthermore, the use of nanocarriers to deliver specific gene inhibitors (eg, BMX siRNA) has been shown to impede tumor growth signals at their source. 210 In addition, the strategy of co-delivering two mRNA vaccines (eg, 5T4 and CD70) has been shown to concurrently enhance antibody-dependent cell-mediated cytotoxicity (ADCC) and T-cell immunity. 211 Concurrently, photothermal and photodynamic therapies physically ablate tumors and, upon light exposure, reprogram TAMs via nanophotodrugs. This results in a conversion of TAMs from the pro-tumor M2 phenotype to the anti-tumor M1 phenotype. Consequently, this reverses the immunosuppressive “cold tumor” microenvironment. 212 Nanoplatforms that are responsive to acidic microenvironments have been shown to activate innate immune pathways by releasing specific immunomodulators. This, in turn, has been demonstrated to reshape the tumor immune microenvironment. 213

Deep Integration of Artificial Intelligence and Computational Nanomedicine

The intricacies inherent in nanomedicine design and the variability among patients pose significant challenges to precision medicine. The integration of artificial intelligence (AI) has been instrumental in disrupting this field, markedly accelerating research and development. 214 Machine learning algorithms can rapidly screen and predict combinations of millions of nanomaterials. They can optimize key parameters such as particle size, charge, and drug loading capacity. Furthermore, they can predict their in vivo release kinetics. Consequently, they have the potential to shorten traditional R&D cycles significantly. 214 The construction of “digital twin” models for patients facilitates the simulation of the distribution, efficacy, and potential toxicity of different nanomedicines within specific patients in a virtual environment. This enables precise prediction and personalized customization of treatment regimens. 215 Additionally, artificial intelligence can efficiently screen for key delivery materials, such as novel ionizable lipids, to construct highly efficient siRNA delivery systems. 216 When combined with patient-derived organoid models, it can simulate real tumor environments in vitro, rapidly validating the accuracy of AI predictions and significantly accelerating clinical translation. 165

Overcoming Clinical Translation Bottlenecks and Promoting Large-Scale Production

The clinical translation of nanomedicines is hindered by two major obstacles: high costs and stringent regulations. Subsequent endeavors will prioritize clinical translation by addressing challenges in production and regulatory review. To address the imperative for scale-up and standardization, there is a need to develop biodegradable polymeric nanogels with enhanced biocompatibility. 217 Furthermore, the establishment of continuous and controllable production processes, such as microfluidics, is essential. Additionally, the formulation of unified standards for physicochemical properties and quality control is imperative to ensure batch-to-batch consistency and stability. 218 To streamline regulatory pathways, it is imperative to advance environmentally friendly, scalable methods, such as green synthesis. These methods have the potential to reduce costs and enhance biocompatibility. Concurrently, establishing a regulatory science framework better suited to the complexity of nanomedicines and standardizing the approval pathway for multifunctional nanomedicines from preclinical development to market launch are key to ultimately benefiting patients. 100

Bio-Inspired and Green Synthesis of Emerging Delivery Systems

The use of natural wisdom in the development of advanced delivery systems has led to novel solutions with considerable promise. Bionic nanocarriers have been shown to possess the capacity for “camouflage”, which involves enveloping tumor or immune cell membranes. This process enables immune evasion and homotargeting capabilities. Moreover, the use of macrophages as “living cell carriers” facilitates penetration of biological barriers and active migration toward hypoxic tumor regions. 100 Conversely, green nanotechnology employs natural resources, including plant extracts and microorganisms, to synthesize metal nanoparticles such as gold and silver. This process is environmentally friendly and cost-effective, and the resulting products exhibit high biocompatibility, offering a new pathway for the sustainable development of nanomedicines. 100

Addressing the Specific Challenges of Prostate Cancer to Achieve Precision Targeting

Subsequent research will place greater emphasis on the unique pathological characteristics of prostate cancer. To address the challenges posed by drug resistance and recurrence, PSMA-targeted nano-PROTAC technology has emerged as a promising approach. This technology involves degrading AR at the protein level, thereby directly overcoming resistance in CRPC. 219 Concurrently, the design of nanovaccines that simultaneously target differentiated tumor cells and cancer stem cells (CSCs) aims to eradicate the root causes of recurrence and metastasis. 150 Moreover, the development of magnetoresponsive nanosystems (eg, GUL@LsiYY1@MZ) can be utilized to induce ferroptosis in tumor cells, thereby effectively eradicating drug-resistant tumor cells. 173 Ultrasonic nanobubbles offer significant advantages in terms of safety and cost-effectiveness. These bubbles can disrupt the blood-prostate barrier via targeted microbubble effects, thereby enhancing the efficiency of gene or drug delivery. 220 The utilization of nanoscale targeted radiopharmaceuticals, exemplified by PSMA-617, facilitates precise, low-toxicity internal radiation therapy for metastatic lesions. Concurrently, non-invasive methodologies, such as photodynamic therapy, can provide localized activation therapy for deep-seated tumors. 220 The integration of liquid biopsy with nanoparticles that effectively capture circulating tumor cells, ctDNA, and exosomes in the blood enables non-invasive early screening, molecular subtyping, and dynamic monitoring of treatment efficacy. 221 For instance, isolating exosome samples for PSA testing can provide early indications of recurrence, 221 while analyzing ctDNA facilitates non-invasive monitoring for the emergence of drug-resistance genes, such as AR-V7. This, in turn, enables the timely adjustment of treatment regimens. The integration of nanotechnology and liquid biopsy signifies a pivotal advancement in the pursuit of precision medicine. 222

Conclusion

In summary, this review has systematically examined nanotechnology applications in prostate cancer across four interconnected domains. First, in the field of diagnosis, nanoparticle-based molecular imaging probes (SPIO for MRI, NIRF nanomicelles for intraoperative guidance) and nanostructured liquid biopsy systems (microfluidic chips, SPR nanosensors) have substantially enhanced detection sensitivity, lymph node metastasis identification, and non-invasive molecular monitoring. Second, in therapeutics, PSMA-targeted liposomes, polymeric nanoparticles, and inorganic nanocarriers have demonstrated improved delivery of chemotherapeutics, gene-editing tools, and immunomodulators. TME-responsive release mechanisms enable spatiotemporally controlled drug liberation. Third, multifunctional theranostic nanoplatforms integrating imaging and therapy have enabled real-time efficacy assessment and personalized treatment adaptation. Fourth, critical analysis of clinical translation—including the instructive failures of BIND-014 and CRLX101, the partial success of AuroLase ® , and the ongoing evaluation of diagnostic probes—has revealed that biological barriers, safety concerns, manufacturing challenges, and regulatory gaps remain formidable obstacles to widespread clinical adoption.

To successfully translate nanotechnology into routine prostate cancer care, concerted efforts will be required across several dimensions. First, the development of smart nanosystems with precise spatiotemporal control is essential. These nanosystems should leverage PSMA and other biomarkers for targeting, as well as TME-responsive mechanisms for controlled release. This will help overcome the heterogeneous EPR effect and achieve consistent therapeutic efficacy. Second, a multimodal synergistic therapy combining chemotherapy, photothermal/photodynamic therapy, and immunomodulation offers the potential to convert immunologically “cold” prostate tumors into “hot” tumors, addressing the limitations of monotherapy and the immunosuppressive bone microenvironment. Third, the deep integration of artificial intelligence and computational nanomedicine promises to accelerate rational nanocarrier design, predict patient-specific responses, and enable personalized treatment optimization. Fourth, it is critical to overcome clinical translation bottlenecks through scalable GMP-compliant manufacturing, harmonized regulatory frameworks, and biomarker-driven patient selection to bridge the gap between preclinical promise and clinical reality. Fifth, sustained investment in bio-inspired and green synthesis approaches will enhance biocompatibility, reduce environmental impact, and potentially lower manufacturing costs. Finally, incorporating prostate cancer-specific considerations—including PSMA heterogeneity, bone metastasis biology, and CRPC resistance mechanisms—into nanocarrier design and clinical trial design will be essential for realizing the full potential of nanotechnology in this disease.

Nanotechnology has the potential to transform the diagnostic and therapeutic paradigms for prostate cancer. By leveraging nanotechnology’s capabilities, we can transform the management of prostate cancer. This transformation will occur through the following mechanisms: enabling real-time molecular imaging, targeted drug delivery with reduced systemic toxicity, simultaneous diagnosis and treatment through theranostic platforms, and dynamic monitoring of treatment response and the emergence of resistance. The result will be a personalized, adaptive strategy for prostate cancer management. The most pressing priorities for clinical translation are as follows: (a) establishing robust biomarkers for patient selection (PSMA expression, EPR effect status, TME characteristics); (b) developing standardized manufacturing processes that ensure batch-to-batch consistency; (c) creating regulatory frameworks that accommodate the complexity of multifunctional nanomedicines; and (d) conducting well-designed clinical trials with biomarker-driven enrichment and clinically meaningful endpoints. If these priorities are addressed, nanotechnology may ultimately deliver on its long-standing promise to improve outcomes for the millions of men affected by prostate cancer worldwide.

Acknowledgments

The author wishes to thank all hands and minds involved in this review.

Abbreviations

ADT, androgen deprivation therapy; AMF, alternating magnetic field; AR, androgen receptor; AUC, area under the curve; CPP, critical process parameter; CQA, critical quality attribute; CRPC, castration-resistant prostate cancer; CTC, circulating tumor cell; ctDNA, circulating tumor DNA; DC, dendritic cell; EPR, enhanced permeability and retention; EMA, European Medicines Agency; FDA, Food and Drug Administration; GMP, Good Manufacturing Practice; GSH, glutathione; HIF-1α, hypoxia-inducible factor-1α; HSPC, hormone-sensitive prostate cancer; ICD, immunogenic cell death; LNP, lipid nanoparticle; LSPR, localized surface plasmon resonance; mCRPC, metastatic castration-resistant prostate cancer; MDCT, multi-detector computed tomography; MDSC, myeloid-derived suppressor cell; MMP, matrix metalloproteinase; MRI, magnetic resonance imaging; MSN, mesoporous silica nanoparticle; NIRF, near-infrared fluorescence; NIR-II, second near-infrared; NPV, negative predictive value; ORR, objective response rate; PAMAM, polyamidoamine; PDX, patient-derived xenograft; PEG, polyethylene glycol; PFS, progression-free survival; PLGA, poly(lactic-co-glycolic acid); PSA, prostate-specific antigen; PSCA, prostate stem cell antigen; PSMA, prostate-specific membrane antigen; PROTAC, proteolysis-targeting chimera; QbD, Quality-by-Design; QD, quantum dot; rPFS, radiographic progression-free survival; SERS, surface-enhanced Raman scattering; siRNA, small interfering RNA; SPIO, superparamagnetic iron oxide; SPION, superparamagnetic iron oxide nanoparticle; SPR, surface plasmon resonance; STEAP1, six-transmembrane epithelial antigen of prostate 1; STING, stimulator of interferon genes; TAM, tumor-associated macrophage; TME, tumor microenvironment; TLR, Toll-like receptor; Treg, regulatory T cell; USPIO, ultra-small superparamagnetic iron oxide.

Data Sharing Statement

Data sharing is not applicable to this article as no data were created or analysed in this review.

Disclosure

The author declares no conflicts of interest in this work.

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