Bacteria-preactivated macrophage membrane-cloaked ZIF-8 nanomissiles boost targeting and PTT/PDT synergy against deep tissue infections

Deep-tissue bacterial infections progress rapidly and recur frequently, while current primary treatment—systemic antibiotics are hampered by poor intralesional exposure, dose-dependent toxicity, and resistance. Thus, precision targeting and mitigating drug resistance have emerged as key breakthroughs for therapeutic efficacy enhancement. Here we reported a biomimetic nanotherapeutic platform—MMZI, that integrated indocyanine green (ICG)-loaded zeolitic imidazolate framework-8 (ZIF-8) with Methicillin-resistant Staphylococcus aureus (MRSA)-preactivated macrophage membrane to enable precise, antibiotic-free phototherapy. In situ encapsulation of ICG within ZIF-8 suppressed aggregation-caused quenching, improved photostability, and boosted photothermal conversion efficiency (PCE) to 47.3% while achieving a 30-fold increase in reactive oxygen species (ROS) generation compared to free ICG. The macrophage membrane cloak, optimized by bacterial preconditioning, conferred immune evasion, biocompatibility, and pathogen-specific affinity which promoted selective accumulation at infected foci and improved bioavailability. Upon near-infrared (NIR) irradiation, MMZI triggered a localized heat/ROS burst that achieved >99% in-vitro bactericidal performance via synergistic photothermal/photodynamic therapies (PTT/PDT). In subcutaneous abscess model, MMZI reduced lesion area by 94.03% (0.29 versus 4.86 mm² in PBS control) and alleviated suppression of tissue repair and angiogenesis, evidenced by a 7-fold increase in Ki67-positive cells and a 6.3-fold increase in CD31-positive vessels. In vivo experiments confirmed the negligible organ toxicity and favorable hemocompatibility of MMZI. By coupling biological recognition with metal-organic framework nanotechnology, MMZI circumvented conventional delivery bottlenecks in deep-seated infections and established a robust, spatiotemporally controllable paradigm for on-demand phototherapy with substantial translational promise.