Novel insight and perspectives of nanoparticle-mediated gene delivery and immune-modulating therapies for pancreatic cancer.

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Introduction

Pancreatic cancer (PCA) is one of the most fatal cancers; the diagnosis is usually not confirmed until advanced stage [ 1 ], which results in mortality closely corresponding to incidence and a miserable five-year survival rate of approximately 10%, further decreasing to 3% in patients with advanced disease. In 2021, there are expected to be 60,430 new cases and 48,220 death [ 2 ]. The traditional treatment options include surgery or chemotherapy, determined by tumor location, local invasion, and metastatic status. Only 15–20% of patients with an early diagnosis have a surgical resection option, and radiation treatment is frequently reserved for resectable tumors and adjuvant contexts. Chemotherapy, including gemcitabine (GEM), 5-fluorouracil (5-FU), and platinum drugs, is often the mainstay in clinical practice. The combination of 5-FU, calcium folinate, irinotecan, and oxaliplatin (FOLFIRINOX) is often regarded as the standard care for patients with metastatic PCA. Despite aggressive chemotherapy, there is severe systemic toxicity even if patients may tolerate the side effects of these drug regimens. However, there is only a slight and transient improvement due to drug resistance [ 3 ].

Treatment failure in PCA has also been linked to the comparative difficulty of drug delivery in reaching cancer cells [ 4 ]. Several attempts have been made to target the tumor stroma and vasculature to increase the delivery and efficacy of PCA therapy [ 5 ]. The development of reliable strategies for efficient drug delivery in PCA has been made possible by significant advancements in nanotechnology [ 6 ]. Compared with conventional options, nanoparticle-mediated drug delivery systems may cross the biological barrier and reach the tumor site, improve the targeting effect of the drug, and significantly enhance the therapeutic efficacy. For example, the combination of albumin paclitaxel nanoparticles with GEM in the treatment of PCA has been shown in various studies to improve drug targeting, increase drug aggregation at the target site, and reduce the dose and toxic side effects, thus improving the survival rate of patients. This combination therapy is much more effective than GEM alone [ 7 ].

Alterations in KRAS have been found in 25% of all human cancers, with pancreatic cancer (90%) being the type of cancer with the highest mutation rates [ 8 ]. Although different strategies have been developed to target this oncoprotein over the last few decades, almost all have failed, relying on the current therapeutic solutions to target proteins involved in the KRAS pathway using chemical or gene therapy [ 9 ]. Nanomedicine can undoubtedly solve the lack of specificity and effectiveness of anti-KRAS therapy.

This review provides new insight into the research progress regarding the PCA tumor microenvironment (TME) and several critical nanoparticle delivery systems for potential treatments in PCA. Additionally, it highlights future perspectives of this novel emerging paradigm in gene delivery and cancer immunotherapy for PCA.

PCA tumor microenvironment

Tumor cells, tumor-associated fibroblasts (TAFs), extracellular matrix (ECM), immune cells, and their released cytokines constitute the TME of PCA. Hypoxia and a subacid TME significantly impact PCA cell growth, invasion, metastasis, and immune escape and affect the antitumor therapeutic effect [ 10 ]. Therefore, regulating the TME and inhibiting tumor development based on new strategies are breakthroughs for PCA treatment. The high desmoplastic stroma of PCA is a critical obstacle for therapy because it reduces systemic medication perfusion and functions as a physical barrier to drug delivery. Furthermore, stroma-tumor interplay creates a distinct TME that promotes tumor development, invasion, immunosuppression, and metastasis [ 11 ].

Extrinsic variables that induce treatment resistance are also abundant in the TME. Combining cellular and acellular components in the TME orchestrates physiological mechanisms that lead to therapeutic resistance. Acellular and abundant ECM components in the TME enhance interstitial fluid pressure (IFP) and blood vessel compression. These tumor characteristics limit drug delivery, resulting in physical resistance and secondary pathophysiological effects, such as acidic pH and chronic hypoxia, which results in hypoxia-induced upregulation of the hypoxia-inducible factor-1α (HIF-1α), Pim-1 proto-oncogene, serine/threonine kinase (PIM1), and sonic hedgehog pathways, as well as changes in the tumor metabolic profile [ 12 , 13 ]. These pathways, in turn, control cell motility and senescence, DNA repair, and altered metabolism, all of which contribute to anticancer drug resistance [ 14 ]. Abnormal cancer cell metabolism is intimately linked to hypoxic environments. The interactions of cellular and acellular elements in the TME create an immunosuppressive microenvironment, resulting in the malfunction and fatigue of therapeutic immune cells [ 15 ].

By upregulating tumor-supporting cells such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), T-regulatory cells (Tregs), fibroblasts, and mast cells in the TME of PCA, cancer cells are ultimately protected from destruction by the immune system. Immune cells such as natural killer (NK) cells and CD8 + T cells act to eradicate tumor cells and are downregulated in the PCA TME (Fig. 1 ) [ 16 ]. The interaction between tumor cells and the TME composition promotes tumor development, progression, invasion, and metastasis [ 17 ].

Fig. 1 The crosstalk of PCA cells communicates with other cells in the TME. For desmoplasia and immune evasion, PCA cells release cytokines and chemokines that attract and activate stromal cells such as cancer-associated fibroblasts (CAFs), MDSCs, TAMs, T-regulatory cells, and pancreatic stellate cells (PSCs). The primary source for ECM deposition is PSCs. By expressing or generating different molecules, such as interleukin 10 (IL-10), transforming growth factor-β (TGF-β), and PD-L1, these cells inside the PCA microenvironment might assist cancer cells in inhibiting CD8 + T cells from overcoming immune surveillance. It was reprinted with permission from Ref. [ 16 ]. Copyright © Chin-King Looi et al. 2019

Advantages of nanoparticle delivery systems for PCA therapy

Recently, the pharmacologic and pharmacokinetic properties that reduce off-target toxicity of anticancer nanodrugs have been improved by rational design, enabling tailored drug administration through passive or active targeting. Moreover, these drug delivery systems clearly showed the potential to overcome problems associated with conventional chemotherapy. They provided more critical improvements in clinical trials (Table 1 ) or in diagnosing and treating diseases [ 18 ].

Table 1 Summary of the clinical trials using nanoparticles for PCA ClinicalTrials.gov ID Agent name Drug Nanoparticles Administration route Phase State Sponsor NCT06048367 Carbon Nanoparticle-Loaded Iron [CNSI-Fe(II)] in the Treatment of Advanced Solid Tumor (CNSI-Fe(II)) CNSI-Fe(II) Carbon Nanoparticle Intratumoral injection 1 Recruiting Sichuan Enray Pharmaceutical Sciences Company NCT00968604 C-VISA BikDD: Liposome in Advanced PCA BikDD BikDD nanoparticle Intravenous injection 1 Withdrawn M.D. Anderson Cancer Center NCT04484909 NBTXR3 Activated by Radiation Therapy for the Treatment of Locally Advanced or Borderline-Resectable PCA NBTXR3 Hafnium oxide-containing nanoparticles Intratumoral injection 1 Recruiting M.D. Anderson Cancer Center NCT02110563 Phase I, Multicenter, Dose Escalation Study of DCR-MYC in Patients With Solid Tumors, Multiple Myeloma, or Lymphoma DCR-MYC Lipid nanoparticles(LNPs) Intravenous injection 1 Terminated (Sponsor decision) Dicerna Pharmaceuticals, Inc., a Novo Nordisk company NCT01300533 A Study of BIND-014 Given to Patients With Advanced or Metastatic Cancer BIND-014 Active-targeting nanoparticles Intravenous injection 1 Completed BIND Therapeutics NCT01437007 TKM 080301 for Primary or Secondary Liver Cancer TKM 080301 LNPs Intra-Arterial Administration 1 Completed National Cancer Institute (NCI) NCT03382340 IMX-110 in Patients With Advanced Solid Tumors IMX-110 a nanoparticle encapsulating a Stat3/NF-kB/poly-tyrosine kinase inhibitor and low-dose doxorubicin 1/2a Active, not recruiting Immix Biopharma Australia Pty Ltd NCT00689065 Safety Study of CALAA-01 to Treat Solid Tumor Cancers CALAA-01 Active-targeting nanoparticles Intravenous injection 1 Terminated Calando Pharmaceuticals

A phase I clinical trial is to evaluate the safety, tolerability, pharmacokinetics (PK) profile, and preliminary efficacy of intratumoral injection of CNSI-Fe(II) in patients with advanced solid tumors, particularly in patients with Kras mutations, e.g., PCA patients ( NCT06048367 ). CNSI-Fe(II) shows promise as an innovative tumor therapeutic agent due to its unique properties of ferroptosis. A phase I open-label dose escalation study assessed the safety and tolerability of BikDD nanoparticles in patients with advanced PCA ( NCT00968604 ). BikDD is a modified gene product that is designed to destroy cancer cells. Delivering BikDD in a fat molecule (a BikDD nanoparticle) may improve the delivery of the gene product into the cells. This may help to stop or slow the growth of PCA. This is the first study using BikDD nanoparticles in humans. NBTXR3 is a new nanosystem formulation by Hafnium Oxide-containing nanoparticles, a first-in-class radio enhancer for pancreatic ductal adenocarcinoma. A phase I study ( NCT04484909 ) showed that NBTXR3 was activated by radiotherapy for locally advanced or borderline resectable pancreatic ductal adenocarcinoma (PDAC).

Lipid-based nanoparticle drug delivery systems for cancer treatment may systematically reduce drug leakage, slow drug release, and significantly reduce side effects on bone marrow and gastrointestinal and hepatic toxicity [ 19 ], which are considered one of the most promising options with good biocompatibility and biodegradability. Approximately 90% of PCA cases have mutations in the significant oncogene K-RAS. Anthiya et al. fabricated functionalized LNPs as a novel anti-KRAS short-interfering RNA (siRNA) therapy. The findings suggest that tLyp-1-targeted LNPs accumulate more in tumors than nontargeted LNPs, implying that a targeting technique may increase the accumulation of siRNA-LNPs and favor tumor reduction [ 20 ].

Polymer micelles refer to the presence of two or more blocks with different chemical structures and properties in a single linear copolymer molecule constituted by chemical bonding (Fig. 2 ) [ 21 ] and enable increased solubility and stability of hydrophobic drugs. The carriers are primarily synthetic, biodegradable, and thermodynamically stable in aqueous media [ 22 ]. At the critical micelle concentration (CMC), amphiphilic block copolymers dissolve in water and spontaneously form a core-shell structure of polymer micelles to complete the solubilization and encapsulation of drugs. Micelles with a low CMC have a prolonged circulation time in the blood and reduce the toxic side effects on normal tissues. Therefore, polymeric micelles are attractive nanocarriers for the delivery of various therapeutic agents. mPEG-PLGA nanoparticles with a core-shell structure may be exploited as an effective drug carrier to deliver hydrophilic and hydrophobic medicines to improve antitumor effects [ 23 ]. Chen et al. prepared a flexible drug-polymer conjugate, PODEA-GemHMI, and integrated it into nanoparticles to deliver the chemotherapeutic GEM and focal adhesion kinase (FAK) inhibitor defactinib. Due to its excellent compatibility, this delivery strategy presents a potential platform for conjugating or encapsulating additional therapeutic agents for treating PCA [ 24 ].

Fig. 2 Strategies to enhance the stability of micelles. ( A ) Decrease the CMC of polymers. ( B ) Enhance the interaction between polymer segments. ( C ) Enhance the interaction between drug and polymer. ( D ) Increase drug loading capacity. Reprinted with permission from Ref. [ 21 ]. Copyright © 2016, Springer Science Business Media Dordrecht

The core-shell structure of inorganic metal nanoparticles is unusual. The core is responsible for particle characterization, such as fluorescence, optical, magnetic, and electronic properties. The shell shields the core from the chemical response to the surrounding environment. It also contains metals or organic polymers that serve as substrates for biomolecule binding. Many types of inorganic metal nanoparticles exist, such as silicon oxide nanoparticles, iron oxide nanoparticles, magnetic nanoparticles, and gold nanoparticles. Gold nanoparticles exhibit distinctive optical and physicochemical qualities, including tiny size, high colloidal stability, high surface area ratio, and accessible synthesis and functionalization. They have been developed as new diagnostic and therapeutic carriers, such as drug delivery systems and radiosensitizers, with negligible systemic toxicity because of their biocompatibility [ 25 , 26 ]. Gold nanoparticles may delicately modify the TME by interfering with the crosstalk between cancer and mesenchymal cells [ 27 ]. Spadavecchia et al. demonstrated that manufactured PEG-AuNPs might be successfully used as nanocarriers for delivering an effective dosage of DOX to PCA cells in a stimuli-responsive manner using a unique active targeting technique in proof-of-concept investigations [ 28 ]. To reduce GEM resistance in PCA cells (PANC-1/GEM) and overcome Triapine’s low solubility, Zhao et al. produced calcium carbonate nanoparticles (CaCO3 NPs) containing Triapine and GEM. CaCO3-GEM-triapine NP nanoformulations increased the therapeutic efficacy of GEM-based chemotherapy by decreasing cancer cell proliferation, migration, and resistance to GEM in both 2D PANC-1/GEM cells and 3D tumor spheroids. The results indicated that PCA medication resistance might benefit from CaCO3-GEM-triapine NPs [ 29 ].

Pluronic-based polymer nanoparticles may be employed for the passive targeting of tumor tissues, lowering the toxicity of medications to healthy tissues because of their small particle size. Antibodies conjugated with small molecules and biotin-modified Pluronic provide the carrier with the property of actively targeting tumor tissues. The resulting polymeric nanoparticle-encapsulated chemotherapeutic drugs may trigger drug release in response to environmental changes in tumor tissues. Meanwhile, some researchers have also prepared dual-targeting Pluronic-containing drug carriers, which have better-targeting effects than individually targeted drug carriers and will further improve the therapeutic effect of drugs [ 30 ].

Nanoparticle-mediated targeted gene therapy for PCA

Due to PCA TME obstacles, conventional chemotherapeutic medicines for PCA have limited intratumoral delivery and distribution efficiency. To address clinical problems in PCA therapy, novel nanotherapeutics such as small molecular medicines, siRNAs, antisense nucleotides, toxins, and antibodies were designed for PCA [ 31 , 32 ], which will provide novel strategies for PCA treatment employing molecular therapeutic techniques.

Gene therapy treats cancer patients effectively and safely by selectively identifying and blocking tumor cells within the body [ 33 ]. Whether activating genes that promote apoptosis or suppressing genes that promote proliferation, gene therapy has significant potential as a PCA treatment. Nanoparticles provide an excellent foundation for integrating desired properties into a single gene delivery device [ 33 , 34 ]. Additionally, nanoparticle surfaces may be functionalized to increase the efficiency of cancer targeting [ 33 ]. In the context of PCA, a possible treatment approach involves using nanoparticles as carriers for siRNA, microRNA (miRNA), and gene augmentation treatment. Currently, most targeted theranostic nanoparticles are under preclinical testing. This section provides an update on gene therapy for PCA based on nanoparticle drug carriers.

Plasmid DNA (pDNA)

A plasmid is a circular double-stranded DNA molecule (pDNA) that may be translated into the intended cell. The replacement of defective genes, the inhibition of tumor-promoting signaling pathway molecules, or the induction of cytotoxicity by proapoptotic and toxin-encoding genes are considered the anticancer mechanisms of pDNA [ 35 ]. pDNA has various benefits for PCA treatment, including excellent specificity and lack of pharmacological resistance [ 36 ]. Senzer et al. delivered a p53 plasmid into specific cells using a cationic liposome, successfully reducing tumor development [ 37 ]. Egorova et al. [ 38 ] described nanoparticles consisting of histidine-arginine-rich peptide and cysteine-crosslinked polymer that were given an iRGD moiety. They described them as pDNA delivery systems for PCA PANC-1 cells and the uterine leiomyoma cell model. Implementing iRGD-modified peptide-based nanoparticles for the cellular delivery of DNA therapies has excellent potential.

CRISPR/Cas9 has the potential to be a gene editing tool. Immunological concerns, limited packing capacity, and poor tolerance limit intracellular delivery vehicles for CRISPR/Cas9. McAndrews et al. [ 39 ] reported a nonviral delivery strategy for CRISPR/Cas9 composed of modified exosomes. The results show that nonautologous exosomes may contain CRISPR/Cas9 pDNA and transfer it to recipient cancer cells to trigger targeted gene deletion using readily accessible transfection reagents. In syngeneic subcutaneous and orthotopic PCA models, CRISPR/Cas9-loaded exosomes may target the mutant KrasG12D oncogenic allele in PCA cells to decrease proliferation and inhibit tumor formation. Exosomes are a potential CRISPR/Cas9 gene editing delivery technology for targeted therapeutics.

Short interfering RNA (siRNA)

siRNA, a double-stranded interfering RNA (RNAi) with a 21–23 nucleotide sequence, was recently delivered by nanoparticle carriers to increase efficacy [ 40 ]. Nanoparticle carriers are critical for successfully delivering siRNA to cells because siRNA is typically swiftly destroyed when injected alone into the circulation [ 41 ]. When siRNA is internalized and integrated with the RISC multiprotein complex to generate the active RNA-induced silencing complex (RISC) in the cytoplasm, it is referred to as a “guide strand” [ 42 ]. The RISC entirely attaches to the mRNA of interest, thereby silencing the gene by blocking mRNA expression via endonucleolytic cleavage [ 42 , 43 ]. siRNA is being utilized to target oncogenes, cell cycle regulatory genes, and growth factors due to its capacity to target many genes [ 40 ].

Superparamagnetic iron oxide nanoparticles (SPIONs) associated with siRNAs targeting cell cycle-specific serine-threonine kinases, polo-like kinase-I (siPLKl-Stav-sPIONs), may be doubly used to deliver siPLK1 to tumors and to assess delivery efficiency in vivo by imaging tumor responses noninvasively. siPLkl-StAv-s were designed and synthesized as therapeutic agents that act through membrane translocation peptides and increase intracellular delivery and tumor specificity by driving endosomal escape-mediated transport to the cytoplasm (myristoylated polyarginine peptide) and tumor-selective peptide (EPPT1), respectively. The tumor-specific siPLK/-StAvSPIONs in the PCA led to the effective silencing of tumor cells and inhibited tumor growth, reduced tumor cell proliferation, and increased apoptosis [ 44 ].

Incorporating siRNA into a nanoparticle carrier has various advantages, including increased tumor targeting, higher cell uptake, extended circulation duration, and decreased immune system recognition of the nanoparticle as a foreign particle, and permits higher accumulation in cancer because of the enhanced permeability and retention (EPR) effect [ 45 ]. Because siRNAs may target single genes and have substantial anticancer effects when targeting altered genes that promote uncontrolled cell proliferation, they may be essential in modulating the TME [ 43 ]. Different nanomaterials may serve as carriers for siRNA delivery. Han et al. [ 46 ] designed a TME-responsive nanosystem using gold nanoparticles coated in PEGylated polyethyleneimine and codelivering all-trans retinoic acid siRNA targeting heat shock protein 47 (HSP47) to retrain PSCs. In addition to preventing ECM hyperplasia, enabling drug delivery to PCA, and dramatically enhancing chemotherapeutic anticancer efficacy, the nanosystem induces PSC quiescence. It was reported that polymer/calcium phosphate/siRNA hybrid micelles or nanoparticles can deliver luciferase siRNA and vascular endothelial growth factor (VEGF) siRNA to enhance accumulation in a PCA mouse model, respectively [ 47 , 48 ]. PLGA polymers have been shown to be potential siRNA delivery vectors due to their low toxicity, prolonged release, and EPR effect [ 49 , 50 ].

Precision treatment with target-specific NPs is a unique strategy for avoiding PCA formation and reducing the evolution of advanced PCA in high-risk individuals while causing no damage to adjacent tissues [ 51 ]. A polymeric nanoparticle-based siRNA delivery system (Local Drug EluteR, LODER) shedding siRNA against mutated KRAS (siG12D LODER) was generated to inhibit mutant KRASG12D, the primary driver mutation in PCA. siG12D LODER resulted in a significant decrease in KRAS levels, and inhibition of proliferation and epithelial-mesenchymal transition impeded the growth of human pancreatic tumor cells and prolonged mouse survival in vitro and in vivo [ 52 ]. The cholecystokinin-B receptor (CCK-BR), a prospective therapeutic target, is missing in the healthy pancreas but is expressed in high-grade PanIN lesions and overexpressed in PCA. To achieve gene therapy, Smith et al. designed a biodegradable nanoparticle polyplex (NP) that preferentially attaches to CCK-BR on PanINs and PCA. The CCK-BR-targeted NP loaded with siRNA to mutant Kras rendered the pancreatic ECM of P48-Cre/LSL-KrasG12D/+ mice less malignant. Targeted NPs decreased metastasis, delayed proliferation, and enhanced survival in mice with extensive orthotopic PCA.

VAV1 protein, which is overexpressed in cancers, especially PCA, stimulates tumor growth and metastasis development, which are related to poor survival. Agbaria et al. anticipated that encapsulating negatively charged siRNA against VAV1 (siVAV1) in PLGA nanoparticles (NPs) and the positively charged antitumor LL37 peptide as a counterion would result in an additional antitumor effect. Suppressing tumor growth and metastasis using an optimal siVAV1 formulation (siVAV1-LL37 NPs) resulted in a significant accumulation of NPs in cancer, which led to an increase in the survival rate. This was caused by lower levels of both VAV1 mRNA and protein. This proof-of-concept investigation supports the idea that encapsulating siVAV1 in NPs with LL37, a substance with both antitumor and counterion functions, will have an additive impact on the treatment of PCA [ 53 ].

Lipid-based nanodrugs offer enormous therapeutic options in cancer diagnosis and treatment. DCR-MYC is an LNP-formulated siRNA oligonucleotide targeting MYC. MYC oncogene activation is essential to the growth of many hematologic and solid tumor malignancies. A phase I clinical trial assessed the safety and tolerability of the investigational anticancer drug DCR-MYC ( NCT02110563 ). A phase I clinical trial to test the safety and effectiveness of TKM-080301 in patients with colorectal, pancreas, gastric, breast, ovarian, and esophageal cancers with hepatic that has not responded to standard treatments. TKM-080301 is a lipid nanoparticle containing siRNA against the PLK1 gene product. For example, biocompatible lipid polymeric hybrid nanoparticles have been utilized to transport HIF-1α siRNA and Gem for subcutaneous and in situ PCA therapy (Fig. 3 ) [ 23 ]. Tumor cells may survive hypoxia by activating multiple signaling channels, of which HIFs are essential transcription factors. Cationic Ɛ-polylysine copolymers (ENPs) absorb surface-negatively charged si-HIF-1α efficiently and enclose Gem within the hydrophilic core. Covering the ENPs with a polyethylene glycol lipid bilayer forms reverse surface charge LENPs. The lipid bilayer of LENPs prevents the agglomeration of nanoparticles and the degradation of si-HIF-1α in serum. These properties enable LENPs to extend the drug encapsulation lifetime in the blood and promote drug release by enhancing vascularity in tumor tissues for better PCA treatment [ 23 ].

Fig. 3 Schematic representation of LENPs codelivering both si-HIF1α and Gem in a PCA mouse model. ( A ) LENP preparation. ( B ) Schematic representation of in vivo blood circulation and tumor cell uptake of LENPs. I: LENPs may protect siRNAs from degradation by serum nucleases, immune recognition, renal clearance, and replacement by other substances in serum. II: LENPs possess high stability and prolong circulation time. III: LENPs can co-deliver si-HIF1α and Gem through the cell membrane into cancer cells for synergistic anti-tumor therapy Reprinted with permission from Ref. [ 23 ]. Copyright © 2014 Elsevier Ltd. All rights reserved

CALAA-01 is a targeted therapeutic designed to inhibit tumor growth and/or reduce tumor size. The active ingredient in CALAA-01 is a siRNA. This siRNA inhibits tumor growth via RNA interference to reduce the expression of the M2 subunit of ribonucleotide reductase (R2). The CALAA-01 siRNA is protected from nuclease degradation within a stabilized nanoparticle targeted to tumor cells. NCT00689065 is a phase I, dose-escalating study of the safety of intravenous CALAA-01 in adults with solid tumors refractory to standard-of-care therapies.

MicroRNAs (miRNAs)

miRNAs are endogenous noncoding RNA molecules with 19–25 long nucleotides in plants and animals. miRNAs affect the expression of numerous protein-coding genes by partially complementary base pairing to mRNA and then silencing the mRNA. miRNAs regulate cell proliferation, apoptosis, differentiation, metabolism, and stress responses. In addition to potential metastatic biological processes, miRNAs may affect adhesion, invasion, migration, epithelial-mesenchymal transition (EMT), and angiogenesis in the TME via many regulatory approaches. Translation repression, degradation, and endonucleolytic cleavage are only a few gene regulatory methods that miRNAs promote [ 43 ]. Because of their association with pathologically relevant gene targets, miRNAs play essential roles in tumorigenesis, progression, metastasis, and treatment effectiveness [ 54 , 55 ]. miRNAs may target several mRNAs rather than just one, as siRNA does, because it only partially complements mRNA in binding. The evidence suggests that lncRNAs may operate as miRNA sponges, regulating the expression of specific genes implicated in cancer development targeted by miRNAs [ 56 ].

Advances in the genetics and biology of PCA therapeutic targets result in genetic markers of great benefit to the prevalence of PCA and involve how protein-coding genes or miRNAs interact with lncRNAs, their function, and their expression. LncRNAs are usually described as RNA transcripts with a length of more than 200 nucleotides but no capacity for protein coding. LncRNAs may mediate tumorigenesis, proliferation, migration, and metastasis by regulating epigenetic modifications, selective splicing, transcription, and protein translation. The RNA encoded by the H19 gene highly expressed in tumor cells is considered a lncRNA sequence. H19 lncRNA is abundant in PCA cells compared to surrounding normal cells. Downregulation of H19 shows PCA progression and cell proliferation, and migration is inhibited when lncRNA H19 and PFTK1 are suppressed by miR-194 expression [ 56 ]. It is not surprising that these lncRNAs may be crucial in the maintenance and regulation of stemness in cancer, given their unique tissue-specific expression and capacity to alter fundamental genomic pathways [ 57 ].

Kumar et al. formulated a PEG block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol-graft-tetraethylenepentamine) block copolymer micelle that carried vismodegib and miRNA in an orthotopic murine model of PCA [ 54 ]. These micelles increased the drug’s elimination half-life and biodistribution of vismodegib. Micelles made of cationic polymers may easily mix with nucleic acids and be taken up by target cells. Micelles may also enhance the targeting and distribution of various payloads to PCA via bioconjugation or inserting functional molecules into the multiblock polymer. A phase I clinical trial to establish the optimal dose of an mRNA encoding human OX40L, IL-23, and IL-36 loaded LNPs to treat solid tumor recurrence ( NCT03739931 ). Furthermore, mRNA-encoded antibodies for LNPs have been reported [ 58 ]. We summarize recent research using nanoparticle gene targeting therapy for PCA in Table 2 .

Table 2 Summary of recent research using nanoparticle gene targeting therapy for PCA Drugs Type of nanoparticle Route of administration Treatment Effect Ref. poly(ethylene glycol)-block-charge-conversional polymer (PEG-CCP)/calcium phosphate (CaP) hybrid micelles micelles Intravenous injection In a siRNA sequence-specific way, intravenously administered hybrid micelles dramatically decreased the luciferase-based luminous signal from spontaneous PCA. The hybrid micelles’ gen-silencing action was associated with their enhanced tumor growth. [ 51 ] LENP-Gem-si-HIF1α biocompatible lipid-polymer hybrid nanoparticles The combination of LENP-Gem-siHIF1 demonstrated considerable anticancer activity. In addition, in an orthotopic tumor model, LENP-Gem-si-HIF1 demonstrated effective inhibition of tumor spread. [ 23 ] scFv-Gem-siBmi-1-NPs Iron oxide nanoparticles (IONPs) scFv-Gem-siBmi-1-NPs transport Gem and siBmi-1 to PCA in a targeted and efficient manner, exerting a corporate antitumor therapeutic effect. [ 59 ] Porous silicon nano drugs loaded with siRNA- circFARSA (pSiNPs-PEI-siRNA-circFARSA) liposomes and porous silicon nanoparticles (pSiNPs) Intravenous injection The PCA cells COLO-357 and SW1990 were considerably suppressed in their development by the combination of pSiNPs-PEI-siRNA -circFARSA, which also significantly reduced circFARSA expression in a dosage-dependent way. Additionally, it dose-dependently reduced the expression of circFARSA. It considerably slowed tumor development in PDX model mice. Compared to Liposome-siRNA- circFARSA, the anticancer function and biosafety of pSiNPs-PEI-siRNA-circFARSA were much more remarkable. [ 60 ] M2-targeted HA-PEI/PEG nanoparticles containing microRNA-125b self-assembled nanoparticles Intraperitoneal injection M1-to-M2 macrophage ratio; M2-targeted HA-PEI/PEG nanoparticles containing microRNA-125b may transfect tumor-associated macrophages in the pancreas, which might have consequences for PCA immunotherapy. [ 61 ] Atu027(Phase IIa) liposome Intravenous injection Precisely silenced PKN3 mRNA expression in the vascular endothelium, potentially inhibiting the tumor’s metastatic expansion. Safe and well tolerated. [ 62 ]

Nanoparticle-mediated immunotherapy for PCA

Intrinsic physical and metabolic stressors increase interstitial fluid pressure, vascular compression, and hypoxia, limiting drug delivery and distribution inside the PCA [ 63 ]. Immunotherapy has recently gained much attention. However, PCA is extremely immunosuppressive and desmoplastic, and the stroma serves as a natural physical barrier preventing tumor tissue from attack by the body’s immune system, which inhibits immunotherapy efficacy [ 64 , 65 ]. Recent developments in nanotechnology have produced clinically relevant multiple nanocarrier platforms that decrease stromal obstruction, improve drug delivery targeting, modulate the stroma to increase immune infiltration, and reactivate immune effector functions to enhance immunotherapy-based strategies for PCA [ 66 , 67 ].

Cancer-associated fibroblasts (CAFs)

Many recent studies have indicated that activated fibroblasts control cancer development by secreting growth factors and ECM as part of their active secretome [ 68 ]. Fibroblasts are persistently stimulated in tumor tissue where “wounds do not heal,” and these “activated” fibroblasts are known as cancer-associated fibroblasts (CAFs). Excessive amounts of VEGF, alpha-smooth muscle actin (α-SMA), and additional proangiogenic factors are the primary components of the tumor stroma and are essential for tumor growth and invasion. These compounds were overexpressed in virtually all solid tumors but not in normal tissue. CAFs produce ECM components such as type I, III, and V collagen and fibronectin. The ECM barriers hurt the efficacy of traditional anticancer therapies such as chemotherapeutic or immunomodulatory medicines. Therefore, CAF-targeted nanoparticles for modifying the TME have attracted much interest.

Blocking CAF activation and proliferation or targeting them for medication delivery might be a novel PCA treatment method. CAF-targeting biodegradable polymer nanoparticles containing α-mangosteen and coated with CREKA peptide were recently reported (Fig. 4 ) [ 69 ]. α-Mangostin modifies the TME by interfering with the TGF-β/Smad signaling pathway and inhibiting CAF activation. In addition, fibronectin overexpressed on the CAF membrane is specifically bound by the CREKA peptide. The combination of the peptide coating and mangostin enhanced CAF inhibition while altering the TME in a way that undermined the stroma barrier, increasing the targeting of CAFs.

Fig. 4 Diagram depicting the modulation of the tumor stroma with the CAF-targeted nanoformulated polyphenol CRE-NP (α-M) followed by the tumor acid-sensitive CRP-MC (Trip). ( A ) Tumor priming by CRE-NP (α-M) effectively lowers bulk ECM synthesis by interfering with TGF-β/Smad signaling pathways. ( B ) The impacts of manipulating the TME include downregulating the main ECM components, normalizing constricted arteries, and increasing blood perfusion. These are all helpful for future nanomedicine accumulation and penetration at the tumor site. ( C ) Intracellular acidity causes the release of triptolide from cancer cells via CRP-MC (Trip) micelles, followed by NRP-1 receptor-mediated endocytosis. Reprinted with permission from Ref. [ 69 ]. Copyright © 2020 Elsevier Ltd. All rights reserved

Tumor-associated macrophages (TAMs)

Macrophages, specialized cells of the mononuclear phagocyte system, are essential for homeostasis, wound healing, tissue regeneration, and immunology. Their primary function is to perform phagocytosis, which may engulf and digest foreign objects, cell fragments, and additional objects not considered regular cells [ 70 , 71 ]. Macrophages become polarized after exposure to various signals, e.g., change into classically M1-activated macrophages and produce IL-12 in response to IFN-γ and lipopolysaccharide (LPS), limiting tumor formation. Following IL-4 or IL-13 stimulation, alternative M2-activated macrophages release IL-10, encouraging tissue repair, wound healing, and cancer development [ 72 – 74 ].

These two active states of macrophages are regarded as “double-edged swords” that may promote and prevent tumor growth [ 75 ]. At the tumor’s initial stage, TAMs, a vital component of the TME, stimulate antitumor immunity. On the other hand, once the tumor has developed, it supports tumor angiogenesis, immune suppression, invasion, and metastasis [ 76 ]. The disparity may be caused by macrophage flexibility, which undergoes polarization state transitions from M1 to M2 in response to changes in the TMEs during tumor formation (Fig. 5 ) [ 77 ]. Reprogramming TAM polarization might thereby impact TAM functions.

Nanoparticles may accurately transport medications to TAMs and regulate the polarized states, overcoming the limitations of traditional TAM-targeted treatments, such as short circulation time, nonspecific delivery, and low drug solubility. They may be beneficial in cancer immunotherapy [ 78 ]. Iron oxide may reshape the TME by changing M2-like macrophages into M1-like macrophages [ 79 ]. The new iron oxide-based nanoparticles may improve therapeutic outcomes by destroying tumor cells and having a long-term immunological impact through immune microenvironment modulation.

Fig. 5 Normal physiological macrophage actions that M2 may promote or M1 inhibit tumor development. Reprinted with permission from Ref. [ 77 ]. Copyright © 2017 Elsevier B.V. All rights reserved

Exosomes are endogenous LNPs. Zhou et al. [ 80 ] showed that disrupting the galectin-9/dectin 1 axis may improve PCA immunotherapy and reverse cancer immunosuppression of M2-like TAMs (M2-TAMs). The delivery system is composed of oxaliplatin (OXA) prodrug as an immunogenic cell death (ICD) trigger, electroporation-loaded galectin-9 siRNA, and bone marrow mesenchymal stem cell (BM-MSC) exosomes, which are mesenchymal stem cells with the ability to differentiate into the bone marrow. BM-MSC exosomes dramatically enhance tumor targeting effectiveness using biomaterials, leading to more significant medication accumulation at the tumor site. iEXO-OXA promotes antitumor immunity by polarizing tumor-suppressive macrophages, recruiting cytotoxic T lymphocytes, and downregulating T-regulatory cells, resulting in considerable therapeutic efficacy in cancer therapy.

The anticancer immune niche was reprogrammed by Gao et al. using an in situ injectable thermosensitive chitosan hydrogel filled with lipid-immune regulatory factor 5 (IRF5) mRNA/C-C chemokine ligand 5 (CCL5) siRNA complexes (LPR@CHG). The LPR@CHG hydrogel increases IRF5 expression while decreasing CCL5 secretion, significantly increasing M1 phenotype macrophages. M1 phenotype macrophages, which develop T-cell-mediated immune responses, govern tumor progression. In general, it is anticipated that the LPR@CHG hydrogel will be an effective immunotherapy platform that may alter the immunosuppressive TME and boost the effectiveness of existing PCA immunotherapies while limiting systemic toxicity [ 81 ]. The TME contains a variety of macrophages, including M1 and M2 phenotypes and TAMs that are either locally proliferating or systemically recruited. Nanomedicine will offer fresh perspectives on cancer immunotherapy with a greater understanding of TAMs when several markers on TAMs are used as targeting ligands on the surface of nanoparticles.

Myeloid-derived suppressor cells (MDSCs)

MDSCs are classified as a diverse population of immature myeloid cells that play an essential role in the TME through immunosuppression. In patients with PCA, the development of monocytes and granulocyte precursors into mature myeloid cells is inhibited, and they are driven to differentiate into MDSCs by tumor-derived substances. It was reported that MDSCs are primarily distributed in bone marrow, lymph nodes, peripheral blood, and tumor tissues and eventually accumulate in the TME [ 82 ]. MDSCs may be divided into granulocytic MDSCs (Gr-MDSCs) and monocytic MDSCs (Mo-MDSCs). MDSCs, particularly Gr-MDSCs, are uncommon in the normal pancreas, and their concentration grows progressively as cancer progresses [ 83 ].

In PCA, MDSCs are critical to the TME’s balance of immunogenic and tolerogenic signals. By inhibiting lymphocyte activity, recruiting Tregs, and expressing immunosuppressive checkpoint molecules, MDSCs inactivate NK cells and CD4 + and CD8 + T cells [ 84 ]. These cells inhibit the growth of cytotoxic T cells, encourage macrophages to adopt an M2 phenotype and attract Tregs through nonspecific and cell-mediated immunosuppressive strategies [ 85 ]. According to recent research, MDSCs are the primary immune cells that inhibit immunity in the immunosuppressive microenvironment of PCA [ 86 ]. Earlier research discovered that low-molecular-weight heparin-D-tocopherol (LMWH) might dramatically decrease G-MDSC recruitment [ 87 ].

The invasion of immunosuppressive cells, mainly MDSCs, was the primary cause of the immunosuppressive microenvironment of PCA. P-selectin glycoprotein ligand-1 (PSGL-1) was initially discovered on the surfaces of MDSCs in PCA [ 88 ]. By interfering with P-selectin/PSGL-1 binding, LMWH may also reduce the recruitment of MDSCs to PCA tissues by affecting the initial stage of the adhesion cascade between vascular endothelial cells (VECs) and MDSCs. It was discovered that a 3-aminophenyl boronic acid-modified low molecular weight heparin-D-α-tocopheryl succinate micellar nanoparticle (PBA-LMWH-TOS NP, PLT NP) might decrease orthotopic PCA and spontaneous metastases. According to the findings, PLT/PTX NPs dramatically improved PCA’s immunological microenvironment and reduced spontaneous metastases. This nanosystem provides a novel platform for modulating the immune milieu and has a wide range of therapeutic applications.

T-regulatory cells (Tregs)

Treg cells, CD4CD25Foxp3 T cells, are a subset of lymphocytes essential for preserving tolerance to self-antigens and benign foreign antigens under physiological conditions. To avoid the host immunological reaction, tumor cells may also use them [ 89 ]. Tregs are a critical immunosuppressive cell subgroup in the TME and impact tumor progression by directly interacting with cancer cells or blocking effector immune cells. Together with other immunosuppressive cells, such as MDSCs, Treg cell processes establish a partly duplicate network that gives tumor immunosuppression resilience and treatment resistance [ 90 ].

Poly(lactic-co-glycolic acid) (PLGA) is a functional, biodegradable, biocompatible polymer. In a humanized mouse model of PCA, a siRNA targeting PD-L1 (siPD-L1) encapsulated in PLGA nanoparticles was recently reported. siPD-L1@PLGA boosted CD8 + T-cell infiltration and significantly reduced tumor development, successfully reducing PD-L1 expression and resulting in a substantial decrease in tumor development [ 91 ]. Dual-therapeutic 5’ ppp dsRNA-encapsulated nanoparticles allowed for a significant stimulation of proinflammatory Th1 cytokine levels, as well as increased proportions of CD8 + T cells over Tregs and M1 over M2 macrophages and lower levels of immunosuppressive B regulatory and plasma cells in TME. As a result, the findings suggest a novel immunotherapy strategy for PCA.

Transforming growth factor beta (TGF-β)

TGF signaling promotes tumor growth via tumor cell autonomy or tumor-stroma interactions and has a tumor-suppressing or tumor-promoting action depending on the cellular setting [ 92 ]. TGF-β suppresses tumor growth in the early phase of PCA by encouraging apoptosis and preventing epithelial cell cycle progression. At the same time, it promotes tumor growth in late-phase PCA by causing genomic instability, neoangiogenesis, immune evasion, cell motility, and metastasis [ 93 ].

As previously stated, the tumor stroma of PCA restricts immunotherapy effectiveness. Wang et al. [ 94 ] reported the development of a pH-responsive clustered nanoparticle (iCluster) containing siPD-L1 and TGF-β receptor inhibitors (LY2157299). At an acidic tumor extracellular pH, iCluster may transfer siPD-L1 and LY2157299 to tumor blood arteries and release PAMAM. As a result, siPD-L1 may reach as much of the tumor tissue as feasible to activate anticancer immunity, and a TGF-β receptor inhibitor may lessen the tumor stroma’s barrier function, enabling more drugs to enter the tumor tissue and activate anticancer immunity. Peng et al. [ 95 ] developed a glutathione (GSH)-responsive mesoporous silica nanoformulation (dMSN-SB), which inhibits intratumoral TGF-β signaling, facilitates tumor-associated neutrophil (TAN) polarization into antitumor N1 phenotypes, and then enhances the PCA response to utilize irreversible electroporation (IRE) and anti-programmed death 1 (anti-PD1) therapy. These findings imply that improving PCA responsiveness to IRE-based immunotherapy by TAN regulation is a potential strategy.

Interleukin-10 ( IL-10)

In many cancers, the TME predominantly suppresses the immune system, blocks antitumor immunity, and causes resistance to immunotherapy. IL-10 is a crucial regulator of the immunosuppressive TME in many mouse cancer types. Reduced IL-12 production by intratumoral dendritic cells due to increased IL-10 synthesis lowers antitumor cytotoxic T-cell responses and posttreatment NK cell activation. Li et al. [ 96 ] designed a gene delivery system producing an IL-10 protein trap to modify the immunosuppressive TME, potentially improving anticancer immunity. To obtain greater and longer-term therapeutic effectiveness in a PCA model, C-X-C motif chemokine ligand 12 (CXCL12) was also delivered to suppress T-cell tumor invasion while concurrently delivering an IL-10 trap. Three injectable lipid-protamine-DNA (LPD) nanoparticles loaded with IL-10 traps and CXCL12 traps decreased tumor formation and greatly extended host life compared to the control groups. In addition, coupled trap gene therapy inhibited immunosuppressive cells such as M2 macrophages, MDSCs, and PD-L1 + cells while promoting immunosuppressive tolerogenic dendritic cells, NK cells, and macrophages intratumorally (Fig. 6 ) [ 97 ].

Fig. 6 LPD nanoparticles contain trap plasmids of IL-10 and CXCL12 for immunotherapeutic effects against PCA. Reprinted with permission from Ref. [ 97 ]. Copyright © 2018 American Chemical Society

We summarize recent research on the use of immunotherapy-based nanoparticles in PCA (Table 3 ).

Table 3 Summary of nanoparticle-mediated immunotherapy strategies for PCA Delivery systems Type of nanoparticle Route of administration Treatment Effect Ref. Nanovesicles or lipid bilayer-covered mesoporous silica nanoparticles containing an immunosuppressive IDO pathway inhibitor lipid bilayer-coated mesoporous silica nanoparticles Intravenous injection Simultaneously, recruiting cytotoxic T cells and Foxp3 + T-cell downregulation can result in significant tumor reduction or eradication. [ 67 ] A dual-immunostimulatory nanoparticle that included both a STING agonist and a TLR4 agonist LNPs It may be taken up by DCs at the tumor location, dramatically increasing the amount of mature DCs and activating PCA’s anticancer immunity. [ 98 ] Mild hyperthermia and immune checkpoint blockade (BMS-202) treatment with size-adjustable thermo and fibrotic matrix-sensitive liposomes (HSA-BMS@CAP-ILTSL) HAS-Liposomes Intravenous injection It considerably slows down tumor development in vivo and reduces the amount of metastatic nodules in distant organs. [ 99 ] Liposome-protamine-DNA nanoparticles encapsulating plasmid encoding CXCL12 and PD-L1 trap LPD nanoparticles Intravenous injection Enhanced T-cell infiltration; improved antitumor response to KPC, allografts, and reduced metastases. Pharmacokinetics and toxicity have both improved. [ 100 ] PEG-PLGA nanoparticles encapsulating ICD inducer oxaliplatin the amphiphilic diblock copolymer nanoparticles Intravenous injection Induced IFN-γ promotes the expression of tumor-infiltrating CD8 + T cells. Nanocarriers improved delivery while lowering toxicity. [ 101 ] Ganglioside-liposome(EPC/EPG/cholesterol-based liposomes) nano vaccine containing WT1 or gp100 antigen targeting CD169 liposome Intravenous injection Liposome internalization by model DC is mediated by CD169. T-cell line with antigen-specific activation. DCs from patients who have been activated. [ 102 ] Peptide-CpG-DNA-liposome lipoplex vaccine encapsulating TM4SF5 antigen liposome Tumor cell suppression through antibody; Prophylactic tumor prevention [ 103 ] Polyethyleneimine-modified aluminum hydroxide nanoparticles aluminum hydroxide nanoparticles Panc02 tumor suppressed. Antigen delivery, cytosolic delivery, and cross-presentation are all enhanced. [ 104 ]

Conclusion

The major causes of the high mortality rate of PCA patients include a shortage of biomarkers, a high recurrence rate, and chemotherapy resistance. Moreover, the two significant microenvironment issues of stroma and hypervascularity result in the complication of PCA management [ 105 ].

Advances in PCA biology have promoted the development of new, rationally designed, molecularly targeted therapeutic approaches. Nanotechnology has proven to be an excellent option for PCA applications. Many types of nanoparticles have been studied in vivo with impressive outcomes [ 106 , 107 ]. Nanoparticles with high stability, high permeability, high retention effect, high targeting, and low toxicity to nontarget tissues allow immune and gene-based agents to act efficiently on target tissues and organs, thus effectively inhibiting tumor growth and metastasis. Researchers have designed various nanoparticles, such as lipid, micellar, and gold nanoparticles, for PCA therapy by elucidating the mechanism of PCA and microenvironmental changes. According to clinical investigations, nanoparticles may be used with immune and gene-based agents and other medications to increase their efficacy while lowering toxicity. Although the long-term adverse effects of these medications are unclear, increasing the efficacy of nanoparticle treatment may effectively increase the overall survival rate and quality of life of patients with PCA. It is promising for applications to treat PCA on a large scale.

There are still many research themes or directions for nanotechnology in future PCA treatment. Generating and implementing nanoparticles with single or multiple functionalities was one of the first directions. Two or more drug combinations, one targeting agent, or several targeting agents are only a few examples of different drug delivery systems. Thus, this kind of drug delivery system will perform a variety of tasks and will be more successful in treating cancer. Multifunctional nanoparticles will be more suitable for clinical translation. Second, any targeted therapy might only benefit some patients due to the heterogeneity of PCA and the emergence of drug resistance. Thus, finding novel molecular signatures or targets exclusively found on cancer cells would be excellent for targeted therapies based on nanotechnology. More innovative packaging technologies are necessary to overcome the obstacles posed by physiological barriers and cancer cells. Finally, although some animal studies have shown that nanoparticles are effective and safe, an additional effect is needed to understand how nanoparticles are cleared from the body and how they interact with molecules in PCA patients. The long-term side effects of using nanoparticles have yet to be determined, and more randomized controlled studies are needed to assess the impact of nanodrugs on PCA patients’ quality of life, all of which should be challenging and need be considered for the future development of nanoparticle-mediated targeted therapy for PCA.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Acknowledgements

The authors are thankful for the research funds from China Medical University.

Author contributions

Wang XQ drafted the English manuscript; Yin X, Li YX, Zhang SH, and Hu ME revised and edited the manuscript; Wei MJ and Li ZH Conceptualization, Project administration, Supervision, Writing-Review & Editing.

Funding

The study was supported by grants from China Medical University’s High-level Talents Research Start-up Fund (#1210619010) and Double First-Class Scientific Research Fund (#3110210603).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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