Tuning protein corona on nucleic acid nanodrugs for targeted delivery

Nanoparticle-based delivery systems hold transformative potential for nucleic acid therapeutics. However, the fate of nucleic acid nanodrugs (NANDs) in vivo differs significantly from that observed in vitro, directly impacting their therapeutic efficacy. Upon introduction into biological fluids, NANDs rapidly adsorb proteins onto their surfaces, forming an assembled adsorption layer known as the protein corona (PC). This PC critically influences the physicochemical properties of NANDs and consequently governs their subsequent biological interactions. This review comprehensively introduces the mechanisms underlying PC formation, including dynamic adsorption kinetics and influential physicochemical and environmental factors. We further discuss how the PC modulates key in vivo processes, including penetration of gastrointestinal mucus and epithelial barriers, stability during systemic circulation, biodistribution and cellular tropism, as well as cellular uptake and endolysosome escape of nucleic acid therapeutics. While the PC may obscure engineered ligands and accelerate off-target clearance, it also offers opportunities to harness endogenous proteins for targeting. We therefore highlight emerging design strategies aimed at actively steering PC composition to achieve targeted nucleic acid delivery and enhanced therapeutic outcomes. Finally, we present prospects for translating fundamental knowledge of PC formation and function into the rational design of next-generation engineered nanocarriers for targeted NANDs applications.