Construction and cytosolic delivery efficiency study of biomineralized albumin/siRNA nanoparticles

Resolving the conflict between cytoplasmic delivery efficiency and biocompatibility of small interfering RNA (siRNA) carriers is crucial for the clinical translation of siRNA therapies. In this study, we developed a highly biocompatible and fully biodegradable siRNA delivery system, MnCO₃@BSA/Zn²⁺/siRNA (MRna), using bovine serum albumin (BSA) and essential metal ions. This carrier leverages the high affinity of Zn²⁺ and Mn²⁺ for biomolecules (BSA and siRNA) to achieve siRNA loading and protection through a water-phase “one-pot” self-assembly and biomineralization process, achieving a 90% siRNA encapsulation rate. Additionally, the nanoscale mineral particles allow rapid disintegration in the endosomal environment to release 55% of siRNA and facilitate its endosomal escape by mediating the “proton sponge effect”. Therefore, the colocalization coefficient of siRNA with the lysosome is only 0.18. Ultimately, MRna loaded with CD47 siRNA effectively reduces CD47 expression at both mRNA and protein levels in tumor cells to lower than 50% of the original, showing efficiency comparable to the commercial transfection reagent Lipo2000. Overall, this study provides a more convenient, efficient and biocompatible strategy for designing siRNA delivery systems.