<p>Infectious tissue damage evolves through a stage-dependent cascade, progressing from initial pathogen invasion and immune dysfunction to subsequent failure in tissue regeneration. While nanotechnology offers promising strategies for infection control, its inability to dynamically adapt to the changing pathological environment remains a limitation. Here, a programmable single-particle core-shell nanoplatform (Z-Lyc@ELP) was constructed by integrating hierarchical structural separation with environment-responsive mechanisms, enabling sequential intervention aligned with infection progression. The outer shell, composed of unsaturated phospholipid-doped garlic-derived exosome-like nanovesicles (GELNs), exhibits reactive oxygen species (ROS) responsiveness. At the early stage of infection, it rapidly releases polymyxin B (PMB) and immunoregulatory molecules to remodel the pathogenic microenvironment. As lesion acidification deepens, the ZIF-8 core gradually decomposes, releasing lycopene (Lyc) and Zn²⁺ ions. This second-wave intervention effectively scavenges excessive ROS, promotes macrophage M2 polarization, and upregulates angiogenic factors, thereby reactivating intrinsic tissue repair. In vivo, the Z-Lyc@ELP nanoplatform achieved a 98.1% healing rate of infectious burn wounds after 16 days and an 80% survival rate in sepsis mice over 10 days. This pathology-guided strategy, combining environment-responsive mechanisms with sequential therapeutic release, offers a dynamic nanoplatform for precise infection treatment and tissue repair.</p> Graphical Abstract <p></p>