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Extracellular Vesicles in Disease / RNA Interference and Gene Delivery · Journal article
Pharmaceutics · August 30, 2026
A consensus or society position rather than new primary data.
This is a comprehensive narrative review of non-viral gene delivery platforms, positioning ionizable lipid nanoparticles as the most clinically mature technology while identifying persistent barriers in endosomal escape, cell-type targeting, and extrahepatic delivery. The review synthesizes the comparative landscape of LNPs, polymeric nanoparticles, inorganic nanomaterials, and engineered extracellular vesicles, offering guidance on current state and future research priorities rather than reporting new clinical or preclinical data.
Journal article.
Ionizable LNPs are currently the most clinically mature non-viral technology, supported by clinical success of siRNA therapeutics and mRNA vaccines, and emergence of in vivo CRISPR therapies. Non-viral vectors offer advantages over viral vectors in cargo capacity, modularity, transient expression, potential repeat dosing, and avoidance of vector–genome integration. Polymeric vectors provide broad chemical tunability but toxicity and batch-to-batch reproducibility remain key concerns.
Polymeric vectors provide broad chemical tunability but toxicity and batch-to-batch reproducibility remain key concerns. Field is transitioning from organ-level delivery toward delivery of correct payload to correct cell type at clinically relevant exposure and safety margin.
Clinicians and researchers should recognize that ionizable LNPs represent the most clinically advanced non-viral platform (evidenced by approved siRNA therapeutics and mRNA vaccines), while polymeric vectors, inorganic nanomaterials, and engineered EVs remain investigational with distinct advantages and unresolved technical barriers. The review signals that the field is prioritizing cell-type selectivity and safety optimization over broader organ-level approaches.
This is a narrative review summarizing the state of non-viral gene delivery platforms, their clinical maturity, barriers, and future directions for researchers and clinicians.
Clinicians and researchers should recognize that ionizable LNPs represent the most clinically advanced non-viral platform (evidenced by approved siRNA therapeutics and mRNA vaccines), while polymeric vectors, inorganic nanomaterials, and engineered EVs remain investigational with distinct advantages and unresolved technical barriers. The review signals that the field is prioritizing cell-type selectivity and safety optimization over broader organ-level approaches.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
What is missing. This record has no reported figures. That is a gap in the analysis, not a judgement about the study.
Gene therapy and genome editing increasingly depend on the safe, effective, and cell-selective delivery of nucleic acids and protein–nucleic acid complexes. Although viral vectors remain important for applications requiring durable gene expression, non-viral vectors offer advantages in cargo capacity, modularity, transient expression, potential repeat dosing, and avoidance of vector–genome integration. Lipid nanoparticles (LNPs), polymeric nanoparticles, inorganic nanomaterials, extracellular vesicles (EVs), and biomimetic hybrid systems have consequently become central platforms for delivery of siRNA, mRNA, plasmid DNA, antisense oligonucleotides, and CRISPR-based genome editors. Among these, ionizable LNPs are currently the most clinically mature non-viral technology, supported by the clinical success of siRNA therapeutics and mRNA vaccines, as well as the emergence of in vivo CRISPR therapies. Nevertheless, efficient endosomal escape, cell-type-selective targeting, extrahepatic delivery, and repeat-dose tolerability remain substantial barriers. Polymeric vectors provide broad chemical tunability, allowing adjustment of charge density, degradability, stimulus responsiveness, intracellular trafficking, and cargo release. However, toxicity and batch-to-batch reproducibility remain key concerns. EVs provide a biologically derived alternative with favorable membrane interfaces and potential advantages for protein and ribonucleoprotein delivery, but their clinical translation is constrained by heterogeneity, loading efficiency, product characterization, and scalable manufacturing. This review summarizes recent advances in non-viral gene-delivery platforms, compares their strengths and limitations, and discusses future directions in cell-selective delivery, endosomal escape, transient delivery of genome-editing machinery, engineered EVs, hybrid vectors, and manufacturing-oriented development. The field is transitioning from organ-level delivery toward delivery of the correct payload to the correct cell type at a clinically relevant exposure and safety margin.
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