From surface chemistry to nuclear targeting: The multifaceted challenge of genetic delivery via inorganic nanoparticles

The delivery of therapeutic genes represents a transformative strategy for the treatment of genetic and complex diseases. Despite the clinical success of viral vectors, their high cost, immunogenicity, and limited cargo capacity underscore the need for safer and more versatile alternatives. Nonviral delivery systems, particularly inorganic nanoparticles, have emerged as promising carriers owing to their structural stability, tunable surface chemistry, and ability to accommodate diverse genetic cargos. This review provides a comprehensive analysis of the multifaceted biological barriers that limit the efficacy of inorganic delivery systems, from extracellular stability and protein corona formation to cell internalization, endosomal escape, and nuclear translocation. We highlight recent advances in the rational design of inorganic nanoparticles (including gold, iron oxide, mesoporous silica, layered double hydroxides, and calcium phosphate) that address these challenges through tailored physicochemical properties, functional coatings, and stimuli-responsive behaviors. Particular attention is given to their applications in gene silencing, genome editing, and nucleic acid–based vaccines, where they act as multifunctional platforms integrating therapeutic and diagnostic capabilities. Although significant progress has been achieved, critical translational hurdles remain, including large-scale reproducibility, long-term safety, and standardized characterization of nanoparticle–biological interactions. Inorganic nanoparticles provide modular, stable, and tunable carriers for nucleic acid delivery, yet their transfection efficiencies typically remain below 10%, substantially lower than viral or lipid delivery systems. Despite significant advances in design and mechanistic understanding, clinical translation has not yet been achieved. Current efforts prioritize niche applications where inorganic systems complement lipid nanoparticles, especially in targeted or multifunctional (theranostic) gene therapies. • Inorganic nanoparticles as emerging nonviral carriers for gene delivery. • Biological barriers critically limit nonviral nucleic acid delivery efficiency. • Structural design and surface chemistry govern cellular uptake and escape. • Inorganic NPs enable multifunctional, imaging, and theranostic gene platforms. • Translation demands standardized synthesis, safety, and regulatory alignment.