Acid/NIR Dual-Responsive Nanoplatform with AND Logic-Gated Controlled Nitric Oxide Release for Companion Theranostics of Tumors

Although nitric oxide (NO) holds great therapeutic potential in oncology, achieving its precise spatiotemporal release and understanding its synergistic molecular actions remain as major challenges. Here, we developed an acid/near-infrared (NIR) dual-responsive nanoplatform (namely, BCN) with AND logic-gated controlled NO release for companion theranostics (CTx) of tumors. BCN is assembled by an acid-responsive photothermal agent (Croc880), a thermoresponsive NO donor (BNN6), and human serum albumin. Specifically, the acidic tumor microenvironment can activate the photothermal effect of Croc880, which subsequently triggers the decomposition of BNN6 and releases the NO. Meanwhile, the acid-responsive fluorescence (FL) and photoacoustic (PA) properties of Croc880 provide real-time NIR-II FL/PA imaging readouts, enabling visualization of the activation process and spatiotemporal guidance of laser irradiation, thereby facilitating imaging-guided CTx. Notably, the released NO disrupts the tumor thermal defense system by inhibiting autophagy and heat shock protein 70 expression. This reciprocal reinforcement between NO signaling and mild hyperthermia results in a strong synergistic effect that effectively eradicates tumors, offering a versatile strategy for the CTx of tumors.