Acceptor Engineering Produces Ultrafast Nonradiative Decay in NIR-II Aza-BODIPY Nanoparticles for Efficient Osteosarcoma Photothermal Therapy via Concurrent Apoptosis and Pyroptosis.

Small-molecule photothermal agents (PTAs) with intense second near-infrared (NIR-II, 1,000 to 1,700 nm) absorption and high photothermal conversion efficiencies (PCEs) are promising candidates for treating deep-seated tumors such as osteosarcoma. To date, the development of small-molecule NIR-II PTAs has largely relied on fabricating donor-acceptor-donor (D-A-D/D') structures and limited success has been achieved. Herein, through acceptor engineering, a donor-acceptor-acceptor (D-A-A')-structured NIR-II aza-boron-dipyrromethene (aza-BODIPY) PTA (SW8) was readily developed for the 1,064-nm laser-mediated phototheranostic treatment of osteosarcoma. Changing the donor groups to acceptor groups produced remarkable red-shifts of absorption maximums from first near-infrared (NIR-I) regions (~808 nm) to NIR-II ones (~1,064 nm) for aza-BODIPYs (SW1 to SW8). Furthermore, SW8 self-assembled into nanoparticles (SW8@NPs) with intense NIR-II absorption and an ultrahigh PCE (75%, 1,064 nm). This ultrahigh PCE primarily originated from an additional nonradiative decay pathway, which showed a 100-fold enhanced decay rate compared to that shown by conventional pathways such as internal conversion and vibrational relaxation. Eventually, SW8@NPs performed highly efficient 1,064-nm laser-mediated NIR-II photothermal therapy of osteosarcoma concurrent apoptosis and pyroptosis. This work not only illustrates a remote approach for treating deep-seated tumors with high spatiotemporal control but also provides a new strategy for building high-performance small-molecule NIR-II PTAs.