Micellar LYTAC-engineered bionic coatings abrogate RANK-dependent osteocatabolism and boost fibrillogenesis-mimetic mineral accretion for empowering osteoporotic osseointegration

Patients with osteoporosis are highly susceptible to fractures that often require implant fixation and stabilization. However, excessive osteoclast activity under osteoporotic conditions accelerates bone resorption at the bone-implant interface, severely compromising implant osseointegration. RANKL-RANK axis is a central regulator of osteoclast function and emerges as a promising target for osteoporosis treatment, yet current therapeutic options primarily rely on reversible ligand neutralization and can be followed by rebound bone loss after treatment discontinuation. Here, we developed a biomimetic titanium implant coating incorporating RANK-targeted micellar lysosome-targeting chimeras (LYTACs) to enhance osseointegration under osteoporotic conditions. Collagen-like peptides (CLPs) were conjugated to bispecific aptamers targeting RANK and the cation-independent mannose-6-phosphate receptor (CI-M6PR) through acid-responsive linkers. The resulting conjugates self-assembled into supramolecular LYTACs (CLP-Apt) and were integrated onto hydroxyapatite-modified titanium surfaces. Hydroxyapatite facilitated mesenchymal stem cell (MSC) recruitment, whereas acidic microenvironmental cues triggered CLP-Apt release. Simultaneous engagement of RANK and CI-M6PR on osteoclasts directed RANK toward lysosomal degradation, thereby suppressing osteoclast-mediated bone resorption while promoting MSC osteogenic differentiation and type H vessel formation. Following lysosomal processing, the released CLPs assembled extracellularly into bone matrix-mimetic fibers that chelated Ca 2+ and accelerated new bone formation through a fibrillogenesis-mimetic process. By directly degrading RANK while promoting vascularized bone regeneration, this coating provides a localized strategy to overcome osteoclast-driven implant failure and achieve rapid, robust osseointegration under osteoporotic conditions.