Pitaya‑inspired compartmentalized microspheres with natural tannic acid-copper coating orchestrate smart release of ions and multi-drugs for synergistic treatment of infected bone defects.

Infected bone defects present a significant clinical challenge, as persistent bacterial burden and exacerbated inflammatory response induce microenvironmental acidification, which severely compromises tissue regeneration. Therefore, this study aims to construct a smart platform to regulate the local microenvironment and achieve the therapeutic effect of bone regeneration. Here, pitaya‑inspired compartmentalized microspheres (IBPR‑CuTA) were developed to provide spatiotemporally controlled pH‑responsive release of Cu 2+ , antibiotic rifampicin (RF) and natural extract icariin (ICA), coupling infection control with tissue regeneration. Specifically, under infected inflammation, the microspheres rapidly release Cu 2+ and RF, which facilitates early anti-bacterial and anti-inflammatory effects and promotes pH normalization. This is succeeded by a delayed release of remaining Cu 2+ to foster angiogenesis, and a subsequent sustained release of encapsulated RF and ICA, collectively providing long-term inhibition of infection recurrence and promotion of bone regeneration. Mechanistically, IBPR‑CuTA was associated with suppressed glucose metabolism-related signaling and TNF/NF‑κB activation, and induced a shift from pro‑inflammatory M1 to reparative M2 polarization. In vivo , IBPR‑CuTA concurrently eradicated infection and accelerated vascularized bone regeneration in an infected defect model. Collectively, these results demonstrate an immunometabolically guided, spatiotemporally programmed microsphere platform that integrates early bactericidal/antioxidant activity with sustained pro‑regenerative cues, highlighting translational potential for managing complex infected bone defects.