Acid-responsive bone-targeting nanoplatform enables spatiotemporal control of osteogenesis and angiogenesis for osteoporosis rescue

Osteoporosis (OP) poses a significant challenge in regenerative medicine due to the lack of therapeutic strategies that can intelligently respond to the local pathological microenvironment for precise intervention. To address this issue, we developed a multifunction-integrated acid-responsive bone-affinitive nanoplatform (Asp6-PSO@MSNs, APS-M) for spatiotemporally coordinated bone regeneration. Hollow mesoporous silica nanoparticles (MSNs) were engineered to encapsulate the osteogenic bioactive Psoralen (PSO), surface-gated by a bone-targeting peptide (Asp6). This sophisticated design serves a dual function: the Asp6 gatekeeper ensures spatial accumulation at hydroxyapatite-rich lesion sites and remains closed at physiological pH, while the acidic microenvironment of osteoclasts triggers "temporal" gate opening for on-demand drug release. Mechanistically, transcriptomics and molecular assays unveiled a dual-mode therapeutic mechanism: the nanoplatform not only ensures high intracellular PSO concentration but also provides bioactive silicon ions from carrier degradation, which collectively robustly activate the PI3K-Akt signaling axis. This activation orchestrates a regenerative microenvironment by coupling osteogenesis (via RUNX2 stabilization) with angiogenesis (via VEGF upregulation), significantly outperforming free drug administration. Consequently, APS-M effectively reversed bone loss, restored microarchitecture, and enhanced biomechanical strength in osteoporotic mice. This work presents a sophisticated "seek-and-treat" nanoplatform that harmonizes the intrinsic bioactivity of silicate materials with targeted pharmacotherapy, offering an effective solution for precision osteoporosis management. STATEMENT OF SIGNIFICANCE: Herein, we report the rational design and synthesis of a new class of acid-responsive nanoreactors by integrating hollow mesoporous silica nanoparticles (MSNs) with surface-adaptive bone-targeting peptides (Asp6). Characterization studies demonstrated an optimal construct (APS-M) with a sophisticated "gatekeeping" capability, showing robust stability at physiological pH and rapid responsiveness to the acidic osteoporotic microenvironment. This optimized nanocarrier was subsequently encapsulated with the osteogenic drug psoralen (PSO). The resulting APS-M system was adequately investigated and shown to effectively synergize osteogenesis and angiogenesis via the activation of the PI3K-Akt signaling pathway. Our work provides new insights into nanoreactor engineering strategies for precision osteoporosis management.