Construction of Multi‐Module RNA Nanoparticles Harboring miRNA, AIE, and CH6 Aptamer for Bone Targeting and Bone Anabolic Therapy

Abstract Bone healing remains a major challenge in the treatment of osteoporosis. Effective strategies that simultaneously promote bone formation and inhibit bone resorption are crucial for the treatment of osteoporosis and associated bone defects. MicroRNA (miRNA)‐based approaches aim at simultaneously promoting bone formation and suppressing bone resorption and have therapeutic potential. However, the toxicity of cationic carriers and off‐target effects are two major challenges associated with miRNA delivery. This study establishes a bone‐targeting miRNA delivery system (CH6‐SNA‐26a) that integrates aggregation‐induced emission (AIE), a CH6 aptamer, and miRNAs into a single nanoplatform without any cationic carrier. In this system, an AIE molecule is coupled to miR‐26a to form a core–shell spherical nucleic acid (SNA‐26a). The CH6 aptamer is co‐assembled with the SNA to achieve specific miR‐26a delivery to the bone surface. This aptamer‐functionalized, non‐cationic miR‐26a delivery strategy (CH6‐SNA‐26a) enables both bone‐targeted delivery and high transfection efficiency, ultimately optimizing bone remodeling and calvarial bone healing in an osteoporosis mouse model while limiting adverse effects in non‐skeletal tissues. Mechanistically, the overexpression of CH6‐SNA‐26a in skeletal tissues promotes bone anabolic action by functionally targeting glycogen synthase kinase 3 beta in bone marrow mesenchymal stem cells and cellular communication network 2 in osteoclasts.