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 Cu2+, antibiotic rifampicin (RF) and natural extract icariin (ICA), coupling infection control with tissue regeneration. Specifically, under infected inflammation, the microspheres rapidly release Cu2+ and RF, which facilitates early anti-bacterial and anti-inflammatory effects and promotes pH normalization. This is succeeded by a delayed release of remaining Cu2+ 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.