Upconversion boosts visible-light-absorbing photothermal agent for 1064-nm-driven photothermal/NO therapy

Current approaches for constructing second near-infrared region (NIR-II) photothermal agents (PTAs) are often constrained by synthetic complexity and limited diversity. Herein, we report an uncommon one-pot, catalyst-free [2 + 2] cycloaddition-retroelectrocyclization [4 + 2] cyano-Diels-Alder reaction that delivers a visible-light-absorbing PTA with a unique molecular skeleton: a tricyclo-bridged ring. To unlock the potential of 520-nm-absorbing PTAs for deep-tissue therapy, these PTAs were combined with upconversion nanoparticles (UCNPs), yielding a composite (UPTA), where UCNPs act as NIR-II-to-visible transducers to excite PTAs. For enhanced therapy, UPTA was further integrated with a thermosensitive nitric oxide (NO) prodrug in a hydrogel, forming gas/photothermal nanocomposites. Both in vitro and in vivo experiments confirmed the potent synergistic antitumor efficacy of NO-combined photothermal therapy. This work introduces a facile synthesis of distinctive PTA structures, and an upconversion-assisted strategy to convert visible-light-absorbing PTAs into NIR-II therapeutics, expanding the PTA library and enabling versatile deep-tissue therapy.