Apigenin based nanoplatform achieves non-small cell lung cancer immunotherapy through glycolysis inhibition and photodynamic co-perturbation of organelles.

Effective treatment of non-small cell lung cancer (NSCLC) remains challenging due to its immunosuppressive tumor microenvironment, metabolic adaptability, and resistance to conventional therapies. To improve the treatment efficiency of NSCLC, we developed a multifunctional apigenin based nanoplatform (MAFE) for synergistic NSCLC therapy. Apigenin, a natural flavonoid with glycolysis inhibitory activity, coordinates with Fe³⁺ to form a metal-phenolic network coating on mesoporous silica nanoparticles, while a dual-organelle targeting photosensitizer was encapsulated within the mesopores. Upon 635 nm laser irradiation, the organelle targeting photosensitizer induces photodynamic disruption of mitochondria and the endoplasmic reticulum, leading to mitochondrial membrane potential collapse and endoplasmic reticulum stress. Meanwhile, apigenin suppresses glycolysis and lactate production, thereby remodeling the immunosuppressive tumor microenvironment. The combined organelle perturbation and metabolic inhibition trigger damage associated molecular patterns release and immunogenic cell death, ultimately activating systemic antitumor immunity. In NSCLC mice, MAFE achieves tumor inhibition rates of 97% for primary tumors and 80% for distant tumors, accompanied by enhanced apigenin bioavailability, effective metabolic reprogramming, and increased effector T-cell infiltration. This work highlights a promising nanoplatform strategy integrating natural product based metabolic regulation with organelle targeting photodynamic therapy for advanced NSCLC immunotherapy.