Calcium phosphate nanoparticles as non-viral gene delivery systems: current advances and challenges

Abstract Calcium phosphate (CaP) nanoparticles have emerged as highly promising systems in nanomedicine due to their excellent biocompatibility, biodegradability, and low immunogenicity. These properties are associated with their close resemblance to the biomineral phase of human bone and teeth, and with the possibility of producing them through bio-inspired synthesis approaches. As a result, synthetic CaP nanoparticles can serve as versatile carriers for a wide range of biomolecules, including peptides, proteins, and nucleic acids. Among these applications, gene therapy has gained increasing attention because of the high specificity and therapeutic potential of nucleic acid cargos such as plasmid DNA (pDNA), messenger RNA (mRNA), and small regulatory RNAs (siRNA and miRNA), for the treatment of numerous diseases. In this context, CaP-based systems represent promising non-viral alternatives to conventional viral vectors, potentially overcoming several limitations associated with viral gene delivery. This review provides a comprehensive overview of recent advances in CaP nanoparticle-based systems for non-viral gene delivery, with a specific focus on their physicochemical properties, nucleic acid loading strategies, and surface functionalization approaches designed to improve colloidal stability, targeting capability, and cellular uptake. Finally, the review critically discusses the major challenges and current limitations that must be addressed to promote the clinical translation of CaP nanoparticles as next-generation gene delivery systems.