A novel NIR-responsive CO gas-releasing and hyperthermia-generating nanomedicine provides a curative approach for cancer therapy

Abstract Light-sensitive nanomaterial-released thermia is an emerging approach for cancer therapy. However, the therapeutic efficacy of this approach is generally modest and several challenging issues remain unresolved, including ineffective conversion from light to heat production, uncontrolled release of anticancer drugs, and non-specific delivery of nanomaterials to the tumor site. Here, we propose a new therapeutic concept by converting a photothermal nanomaterial to tumor cell-killing gas in the tumor microenvironment (TME) for gasothermal therapy. This novel strategy employed a chemical coordination (BPN-MnCO) between light-sensitive black phosphorous nanomaterial (BPN) and metal carbonyl (MnCO). The absorption of near-infrared red (NIR) light by BPN triggered the photochemical degradation of coordinated MnCO to produce a high concentration of carbon monoxide (CO) as well as hyperpyrexia in the local TME. Additionally, the surface coordination of MnCO protected BPN from biodegradation to achieve a long-lasting effect of heat production, which went through a feedback mechanism to effectively produce anticancer CO. In various preclinical cancer models, we showed that this approach nearly completely eradicated tumors without causing any notable adverse effects. Mechanistically, we discovered that BPN-generated heat inhibited the repair process of the CO-induced DNA damage and thus accelerated the ATM–GADD45–P53–Cyclin B cell death signaling. In summary, we provide compelling experimental evidence to support our new concept of gasothermal anticancer therapy that is likely to shift a new paradigm for effective treatment of cancer.