Jul 2026· ACS Applied Materials and Interfaces· Vol 18, pp. 40122-40157· 0 citations· 189 references
Medicine
TL;DR
This review systematically dissects how functional polymer engineering-including interfacial shielding, targeted ligand modification, membrane perturbation, and stimuli-responsive disassembly-facilitates systemic circulation, antigen-presenting cell uptake, endosomal escape, and intracellular cargo release.
Abstract
Nucleic acid vaccines have emerged as revolutionary platforms for infectious disease prevention and cancer immunotherapy. However, their clinical translation is significantly hindered by sequential biological barriers, necessitating highly efficient delivery systems. Biomedical polymers, owing to their tunable physicochemical properties, versatile structural engineering, and robust biocompatibility, have become a cornerstone in the development of nucleic acid nanocarriers. This review provides a comprehensive overview of polymeric delivery vehicles for nucleic acid vaccines, with a specific focus on rational design strategies tailored to overcome complex physiological barriers. We systematically dissect how functional polymer engineering-including interfacial shielding, targeted ligand modification, membrane perturbation, and stimuli-responsive disassembly-facilitates systemic circulation, antigen-presenting cell uptake, endosomal escape, and intracellular cargo release. Furthermore, we critically examine the persistent bottlenecks in current delivery platforms, such as the restricted uptake in primary immune cells and the fundamental inefficiencies of endosomal escape, while outlining future perspectives for the development of next-generation, clinically translatable polymeric nucleic acid vaccines.
RNA vaccines have emerged as an attractive platform for treating infectious diseases, cancer immunotherapy, and personalized medicine; however, their clinical success depends on multiple factors, including efficient, stable, and scalable delivery systems. Because RNA molecules are highly sensitive to factors such as enzymatic degradation, oxidation, poor cellular uptake, and limited endosomal escape, nanocarrier platforms play essential roles in protecting RNA cargo and enabling effective intracellular delivery. The biological performance of RNA nanocarriers depends on efficient cellular uptake, endosomal escape, intracellular RNA delivery, biodistribution, and immune modulation. Comparative assessment emphasizes that lipid nanoparticles remain the most clinically mature approach, while nanostructured lipid carriers, polymeric systems, and exosome-based nanocarriers provide multiple benefits for stability, targeted delivery, biocompatibility, and/or controlled release. Translational challenges involving GMP manufacturing, batch reproducibility, regulatory expectations, and scale-up are considered critical for effective nano-based RNA vaccine delivery and are elaborated in this review. Emerging advances such as pKa-tuned ionizable lipids, ligand-targeted systems, stimuli-responsive nanocarriers, circular and self-amplifying RNA platforms, artificial intelligence-guided formulation design, and needle-free delivery technologies may further expand the safety, accessibility, and therapeutic potential of RNA vaccines. In this review, we highlight next-generation nanocarrier systems for RNA vaccines, with an emphasis on novel nanocarrier RNA vaccine delivery systems. Additionally, we evaluate stability engineering approaches that currently limit global vaccine distribution and the future of the nanocarrier platforms for RNA vaccines.
Mohannad M. Fallatah, Samiyah Al-Khaldi, Dimah K. Alrabiah et al.· Pharmaceutics· 0 citations
Small interfering RNA (siRNA) therapeutics have emerged as a transformative approach for sequence-specific gene silencing, offering the potential to treat a broad spectrum of diseases by selectively suppressing disease-associated genes. However, the clinical translation of siRNA remains limited by rapid enzymatic degradation, poor cellular uptake, inadequate endosomal escape, and off-target effects, necessitating the development of efficient delivery systems. Extracellular vesicles (EVs) have gained considerable attention as natural nanocarriers owing to their excellent biocompatibility, low immunogenicity, intrinsic targeting capability, and ability to protect therapeutic cargo while traversing complex biological barriers. This review comprehensively discusses the biological characteristics of EVs, the molecular basis of RNA interference, and the major challenges associated with siRNA delivery [Fig. 1]. Recent advances in EV engineering, including cargo-loading strategies such as electroporation, sonication, extrusion, parent-cell engineering, and microfluidic approaches, together with surface functionalization using peptides, antibodies, aptamers, and hybrid nanoplatforms, are critically evaluated for improving targeting specificity and intracellular delivery. Furthermore, the therapeutic applications of engineered EV-mediated siRNA delivery in cancer, neurological disorders, liver diseases, cardiovascular diseases, inflammatory disorders, and infectious diseases are systematically summarized, highlighting their potential to enhance gene silencing while minimizing systemic toxicity. Current challenges related to large-scale manufacturing, cargo-loading efficiency, standardization, quality control, regulatory approval, and clinical translation are also discussed, together with emerging technologies involving synthetic biology, genome engineering, artificial intelligence, and multifunctional hybrid vesicles. Overall, engineered extracellular vesicles represent a highly versatile and biologically inspired platform for targeted siRNA delivery, providing a promising foundation for the development of next-generation precision RNA therapeutics and accelerating the clinical translation of gene-silencing strategies.
G. S. Amrish Varshan, S. Namasivayam· Nanomedicine: Nanotechnology...· 0 citations
Gene delivery is a highly advanced therapeutic approach that involves the introduction of therapeutic nucleic acids, including DNA and RNA, into target cells to restore, regulate or enhance cellular function. Delivery vectors are a critical determinant of gene therapy efficacy and are generally classified as either viral or non-viral. Viruses vectors are often transfection efficient, but the clinical applications are limited by concerns such as immunogenicity, limited cargo capacity and manufacturing complexity. In contrast, non-viral vectors provide higher safety, structural versatility and ease of production but often have lower delivery efficiency and encounter various extracellular and intracellular barriers. Recent advances in nanotechnology have enabled the development of a variety of nanocarriers that can partially overcome these limitations and improve the performance of gene transfer. Protection of nucleic acids from degradation, selective delivery to target cells with minimal uptake by healthy tissues, efficient cellular internalization and intracellular release of the genetic cargo are among the major challenges in gene delivery. Functionalization of nanocarriers is a promising strategy to overcome these barriers, enhancing nucleic acid loading, colloidal stability, biocompatibility, targeting ability, endosomal escape and overall transfection efficiency. This review summarizes the different functionalized nanocarriers for gene delivery such as silica-based nanoparticles, gold nanoparticles, magnetic nanoparticles, graphene-based materials, carbon nanotubes, polycationic systems, and lipidic nanostructures. Special emphasis is placed on the role of surface functional groups and ligands in modulating biological performance and overcoming delivery barriers. The studies reviewed here all show that functionalized nanocarriers are generally better than their non-functionalized counterparts, but their effectiveness strongly depends on the composition of the nanocarrier, the surface chemistry, the nature of the cargo and the context of the target cell. Overall, functionalized nanostructures are promising platforms for improving the safety and efficiency of non-viral gene delivery. .
Houra Nekounam, Ali Karbalaeimahdi, Faranak Mohammadi et al.· Nanotechnology· 0 citations
This article provides a comprehensive overview of the evolving landscape of nucleic acid-based therapeutics and aims to inform clinicians, researchers, and pharmaceutical scientists about their current applications and future potential in modern healthcare.
Satyaraj Ombase, Shanmugarathanam Alagarsamy, R. Prasad et al.· Adolescência e Saúde· 0 citations
A structured translational roadmap is proposed that prioritizes biologically predictive design, fit-for-purpose safety assessment, scalable good manufacturing practice production, early regulatory alignment, and clinically meaningful benefit over unnecessary structural complexity.
Yi Li, Rui Luo, Yuxuan Li et al.· Biomedicine & pharmacotherap...· 0 citations
The integration of rational material design, high-throughput screening, artificial intelligence, and interdisciplinary collaboration will be essential to advance next-generation targeted in vivo mRNA cell therapies toward clinical translation.
Danyang Wang, Yumin Li, Jinfeng Deng et al.· Drug Delivery· 0 citations
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