Immune-smart nanocarriers for nucleic acid oncology: engineering biomaterials for safe, precise, and durable responses.

Nucleic acid therapeutics, including messenger RNA, small interfering RNA, antisense oligonucleotides, and gene-editing platforms, have emerged as highly effective and promising tools in oncology because they directly regulate oncogenic pathways. However, rapid degradation, poor cellular uptake, off-target effects, and undesired immune activation limit their clinical application. To overcome these challenges, researchers have developed immune-smart nanocarriers that integrate advanced biomaterial engineering with immunological functionality. These nanocarriers protect labile nucleic acids, evade immune recognition and clearance, and deliver therapeutic payloads selectively to cancer or immune cells with precise spatial and temporal control. By incorporating stimulus-responsive components, surface ligands, and immune-modulatory features, smart nanocarriers can sense tumor microenvironment signals and regulate payload release, thereby enhancing therapeutic efficacy while minimizing systemic toxicity. Furthermore, optimized nanocarrier size, charge, and composition can effectively modulate immune responses, prevent immune suppression, and induce durable anticancer immunity. Recent advances have highlighted the successful integration of nucleic acid therapeutics with cancer immunotherapy strategies, including immune checkpoint modulation and personalized cancer vaccines, using lipid-based, polymeric, and hybrid nanocarrier systems. This review discusses the fundamental principles of immune-smart nanocarriers for nucleic acid-based oncology, recent developments in biomaterials and their biomedical applications, and the major challenges associated with achieving safe clinical translation, prolonged targeting, and high therapeutic efficacy for personalized anticancer treatment.