Acceptor-planarized type Ⅰ photosensitizer for lipid droplet-targeted two-photon photodynamic therapy by ferroptosis

Two-photon photodynamic therapy(TP-PDT) has garnered significant attention because of its excellent depth of tissue penetration and high spatiotemporal selectivity. However, the limited targeting ability and oxygen dependency of photosensitizers(PSs) significantly hinder the effectiveness of photodynamic therapy in hypoxic tumor treatment. Herein, we designed and synthesized two lipid droplet(LD)-targeted two-photon PSs(TBPCP and TBCP) by reducing benzene rings to achieve “acceptor planarization”. Notably, acceptor planarization not only enhanced the intramolecular charge transfer but also transferred the photochemical reaction from type Ⅱ(TBPCP) to type Ⅰ(TBCP). Under the irradiation of 940 nm femtosecond pulsed laser,TBPCP and TBCP showed bright two-photon-excited fluorescence and excellent LD targeting in living cells. Comparing TBPCP(type Ⅱ PS), the outstanding TP-PDT efficacy of TBCP(type Ⅰ PS) under hypoxic conditions could be obtained in both cellular experiments and multicellular tumor spheroids(MCTS) model. Additionally, both TBPCP and TBCP could induce the lipid peroxidation in the type Ⅰ or type Ⅱ PDT due to the location of LD, depleting GSH and inactivating GPX4 to induce nonprogrammed ferroptosis in cells.