An ROS-responsive photosynthetic biosystem disrupts the infectious-inflammatory-hypoxic cycle in pneumonia

Abstract Acute lung injury (ALI) is sustained by a self-reinforcing cycle of inflammation, oxidative stress and hypoxia that current therapies cannot fully disrupt. To break this cycle, we engineered Haematococcus pluvialis (Hae) with chemiluminescent peroxyoxalate (CPPO) and fluorophore (Cy5) to construct a ROS-responsive photosynthetic biosystem (Hae@CC) for ALI therapy. Upon nebulization, excess H2O2 at the lesion triggers chemiluminescence (CL), which activates Cy5 through resonance energy transfer and drives endogenous Hae photosynthesis to produce oxygen (O₂) and the antioxidant astaxanthin (AST). In both lipopolysaccharide (LPS)- and bacteria-induced murine ALI models, aerosolized Hae@CC reduces bacterial load, alleviates pulmonary oedema and inflammation, promotes M2-biased macrophage polarization, enhances angiogenesis and improves pulmonary function, outperforming dexamethasone across multiple endpoints, with no appreciable toxicity in vivo. By correcting local hypoxia and redox imbalance, this biosystem resets the alveolar microenvironment, establishing that restoring homeostatic control, rather than blocking individual mediators, resolves inflammatory tissue injury.