Light‐Induced Self‐Escape of Spherical Nucleic Acid from Endo/Lysosome for Efficient Non‐Cationic Gene Delivery

Abstract Developing non‐cationic gene carriers and achieving efficient endo/lysosome escape of functional nucleic acids in cytosol are two major challenges faced by the field of gene delivery. Herein, we demonstrate the concept of self‐escape spherical nucleic acid (SNA) to achieve light controlled non‐cationic gene delivery with sufficient endo/lysosome escape capacity. In this system, Bcl‐2 antisense oligonucleotides (OSAs) were conjugated onto the surface of aggregation‐induced emission (AIE) photosensitizer (PS) nanoparticles to form core–shell SNA. Once the SNAs were taken up by tumor cells, and upon light irradiation, the accumulative 1 O 2 produced by the AIE PSs ruptured the lysosome structure to promote OSA escape. Prominent in vitro and in vivo results revealed that the AIE‐based core–shell SNA could downregulate the anti‐apoptosis protein (Bcl‐2) and induce tumor cell apoptosis without any transfection reagent.