A multifunctional ICAM1-directed MnO₂@ZIF8 nanoplatform with Tanshinone IIA synergistically reverses senescence and restores alveolar regeneration in septic lung injury.

Sepsis-induced acute lung injury (ALI) is characterized by severe oxidative stress and senescence of alveolar type II epithelial cells (AECⅡ), yet effective therapies capable of reversing these pathological processes remain lacking. We developed a multifunctional ICAM1-targeted MnO2@ZIF8 nanoplatform encapsulating Tanshinone IIA (TSA) that integrates selective targeting, redox regulation, and senescence reprogramming. The nanoplatform preferentially accumulated in inflamed lung regions, efficiently scavenged reactive oxygen species (ROS), activated the Nrf2-mediated antioxidant pathway, and suppressed the IL-33/ST2 inflammatory axis. Single-cell RNA sequencing revealed that treatment reshapes AECⅡ differentiation trajectories, suppresses senescence-related transcriptional signatures, and enhances alveolar regenerative potential by restoring stem-like phenotypes. Proteomic and metabolomic analyses further confirmed improved mitochondrial metabolism, SASP modulation, and inflammatory resolution. Functionally, Anti-ICAM1-MnO2@ZIF8@TSA restored alveolar structure, boosted oxygenation, and markedly increased survival in CLP-induced septic mice. Collectively, these findings present a nanobiotechnological strategy that rejuvenates senescent epithelial cells and provides a mechanistically guided therapeutic approach for the treatment of sepsis-associated pulmonary failure.