Natural Killer Cell Membrane-Cloaked Virus-Mimicking Nanogenerator with NIR-Triggered Shape Reversal and center dot C/center dot OH Storm for Synergistic Thermodynamic-Chemodynamic Therapy

Free radical-based anticancer modality has been widely applied to cancer therapies. However, it still faces challenges of low delivery efficiency and poor selectivity of free radical generation specifically toward tumors. Herein, a virus-mimicking hollow mesoporous disulfide-bridged organosilica is designed to encapsulate center dot C precursor 2, 2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH), which is then enclosed by tannic acid (TA)/Fe-III photothermal assembly and further cloaked by natural killer (NK) cell membrane to achieve synergistic thermodynamic-chemodynamic therapy. The nanogenerator can first evade immune surveillance via NK cell membrane "cloaking" mechanism to strongly accumulate in tumors. Interestingly, the NIR laser-induced heat can trigger NK cell membrane rupture for "shape reversal" to expose a virus-like surface to amplify the cellular uptake, and simultaneously break the azo bonds of AIPH for in situ controlled center dot C generation. Then upon glutathione (GSH) triggering, the nanogenerator disintegrates via disulfide-thiol exchange and efficiently generates center dot OH by lysosomal pH-initiated TA-Fe-III reaction; notably, the consumption of GSH can amplify oxidative stress to enhance free radical therapy by weakening the self-defense mechanism of tumor cells. It is envisioned that the NK cell membrane-cloaked virus-mimicking and NIR/GSH sequentially activated center dot C/center dot OH radical nanogenerator can provide a promising strategy for oxidative stress-based anticancer therapy.