Jul 2026· International Journal of Nanomedicine· Vol 21, pp. 1-29· 0 citations· 246 references
Medicine
TL;DR
The potential of non-viral vectors to overcome the inherent limitations of viral delivery and to drive the development of next-generation gene therapy approaches that are safer, more adaptable, and clinically relevant is underscored.
Abstract
Abstract Gene therapy has emerged as a transformative strategy for treating a wide range of genetic and acquired disorders. Despite its potential, clinical translation is hindered by the limitations of viral vectors, including immunogenicity, insertional mutagenesis, limited cargo capacity, and production challenges. Consequently, non-viral gene delivery systems have gained increasing attention as safer, more versatile alternatives. These platforms, including lipid-based nanoparticles, polymers, dendrimers, inorganic nanocarriers, and hybrid systems, offer customizable physicochemical properties, scalable manufacturing, and reduced risk of adverse immune responses. This review systematically expresses recent advances in non-viral vectors, focusing on the key parameters that influence cellular uptake, endosomal escape, nuclear localization, and overall transfection efficiency in various disease, especially cancers. Additionally, we evaluate recent preclinical and clinical studies, highlighting promising translational outcomes and therapeutic applications. By comparing different non-viral strategies and discussing their mechanistic underpinnings, this review underscores the potential of non-viral vectors to overcome the inherent limitations of viral delivery and to drive the development of next-generation gene therapy approaches that are safer, more adaptable, and clinically relevant.
Despite their promise, significant challenges remain, including low cargo-loading efficiency, batch heterogeneity, limited scalability and the absence of standardized manufacturing and regulatory frameworks, future research must address these barriers to accelerate the clinical translation of exosome-based therapeutics.
Elza Karabagh, Babek Alibayov, Adil Allahverdiyev· Expert Reviews in Molecular...· 0 citations
RNA therapeutics have emerged as versatile platforms for gene modulation and protein expression in vaccination, oncology, genetic disorders, and inflammatory diseases. However, their broader clinical application remains limited by inefficient delivery, insufficient tissue specificity, inadequate intracellular bioavailability, and long-term safety concerns. This review examines non-viral and non-lipid RNA nanocarriers from mechanistic and translational perspectives. We outline the cargo-specific delivery requirements of various RNA modalities and analyze polymeric nanoparticles, inorganic nanomaterials, peptide- and protein-based carriers, and virus-like particles as distinct strategies to overcome extracellular, tissue-level, cellular, and intracellular barriers. Cross-platform trade-offs are evaluated based on RNA association and release, cargo compatibility, administration route, biodegradability, immune interactions, and manufacturability. We further discuss how carrier architecture influences biodistribution, intracellular RNA activity, and therapeutic efficacy across major disease areas. Clinically validated lipid nanoparticle (LNP) formulations serve as translational benchmarks, while non-lipid systems are evaluated based on productive delivery, release efficiency, repeat-dose compatibility, long-term material fate, scalability, and regulatory feasibility. By integrating cargo requirements, barrier resolution, intracellular trafficking, and translational benchmarking, this review highlights non-viral and non-lipid nanocarriers as complementary platforms for context-specific RNA therapy.
Mingxia Jiang, Qiannan Cao, Huapan Fang et al.· Journal of Controlled Releas...· 0 citations
Gene therapy has emerged as one of the most promising approaches in both medical and biotechnological fields due to its capacity to modify, optimize, and regulate target DNA sequences. Recent advancements integrating gene therapy with nanotechnology, particularly through nano-carrier systems, have enabled precise delivery of therapeutic nucleic acids with controlled release at specific pathological sites [1]. Initially focused on monogenic disorders, gene therapy applications have now expanded to a broad spectrum of inherited and acquired diseases [2]. Protein-based nanocarriers have attracted considerable attention as next-generation non-viral vectors due to their intrinsic biocompatibility, biodegradability, and structural versatility [3]. Their ability to encapsulate nucleic acids, support controlled release, and enable targeted delivery makes them attractive candidates for cancer gene therapy. These unique characteristics position protein-based nanocarriers as a cell-friendly and effective strategy for improving the safety and efficiency of gene delivery systems [4]. Consequently, they represent a promising strategy for improving the safety and efficacy of cancer gene therapy. The development of safe, efficient, and biocompatible vectors remains a critical determinant of therapeutic success. Recombinant peptides, despite their therapeutic potential, face challenges such as high toxicity, instability, poor bioavailability, and costly production, which gene therapy strategies aim to overcome [5]. Techniques including gene knockdown, mutation correction, and gene insertion are central to modern gene therapy approaches. This article reviews the recent progress and challenges associated with nano-based non-viral vectors designed for targeted delivery of DNA into cancerous cells.
M. Yousefian, Maryam Baharmast· Journal of Biomaterials Scie...· 0 citations
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.
Pijun Su, Huilin Yuan, Kangxin Zhang et al.· ACS Applied Materials and In...· 0 citations
This review provides a comprehensive overview of the current status of viral and non-viral vector systems for in vivo and ex vivo applications, and key comparisons are made across safety, efficacy, scalability, and immune responses.
INTRODUCTION
Nanoparticle-based drug delivery has emerged as a transformative approach in modern therapeutics, offering improved targeting efficiency, enhanced pharmacokinetics, and reduced systemic toxicity compared to conventional drug delivery systems.
AREAS COVERED
This review comprehensively examines major nanocarrier platforms, including lipid-based, polymeric, inorganic, and hybrid systems, with emphasis on their structural design and functional properties. It further explores current advancements in targeting strategies, including passive targeting via the enhanced permeability and retention (EPR) effect and active targeting through ligand-receptor interactions involving antibodies, peptides, aptamers, and small molecules. Key biological and technological barriers to clinical translation are also discussed, such as tumor heterogeneity, abnormal vasculature, dense extracellular matrix, immune clearance, and limited cellular uptake. Additionally, emerging stimuli-responsive systems, including pH-, redox-, and enzyme-sensitive nanocarriers, are highlighted for their role in controlled and site-specific drug release.
EXPERT OPINION/COMMENTARY
Despite significant progress, the clinical translation of nanomedicine remains constrained by biological complexities and scalability challenges. Future advancements integrating biomimetic strategies, multifunctional design, and artificial intelligence-driven modeling are expected to enhance targeting precision, biocompatibility, and translational success.
Nithya Ajay, Anu Shibi Anilkumar, R. Veerabathiran· Therapeutic delivery· 0 citations