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 non-programmed ferroptosis in cells.

双光子光动力疗法（TP-PDT）因其出色的组织穿透深度和高时空选择性而受到广泛关注。然而，光敏剂（PS）有限的靶向能力和氧依赖性严重阻碍了光动力疗法在缺氧肿瘤治疗中的有效性。在此，我们通过减少苯环来设计并合成了两种脂滴（LD）靶向双光子PS（TBCPP和TBCP）以实现“受体平面化”。值得注意的是，受体平坦化不仅增强了分子内电荷转移，而且还将光化学反应从II型（TBCP）转移到I型（TBCP）。在940 nm飞秒脉冲激光照射下，TBPCP和TBCP在活细胞中表现出明亮的双光子激发荧光和优异的LD靶向性。与TBCP（II型PS）相比，TBCP（I型PS）在低氧条件下在细胞实验和多细胞肿瘤球（MCTS）模型中均能获得出色的TP-PDT疗效。此外，由于LD的位置，TBCPP和TBCP都可以在I型或II型PDT中诱导脂质过氧化，消耗GSH并使GPX4失活，从而诱导细胞中的非程序性铁死亡。