Nanocarriers Based on NaTmF₄:0.5%Er³⁺@NaLuF₄ Upconversion Nanoparticles with Enhanced Near-Infrared Luminescence for Combination Tumor Treatment

Combination therapy could significantly improve the therapeutic effect of tumors. However, due to the lack of reasonable integration of different treatment modes, it is difficult to maximize the effect of combination treatment. To solve this problem, by adjusting the dosage of NH 4 F/NaOH, we developed NaTmF 4:0.5%Er 3+ @NaLuF 4 upconversion nanoparticles with strong near-infrared luminescence. On this basis, nanocarriers (USFH-CI) encapsulated with high-loading (33.35%) Fe(acac) 3, wrapped by human serum albumin, and grafted with cinnamic aldehyde (CA) and the IR780 photosensitizer were constructed. The dense extracellular matrix (ECM) in tumor tissues prevented the drug from diffusing into the tumors. Once USFH-CI nanocarriers were delivered to the tumor area, CA pH-responsively released H 2 O 2, which promoted photothermal therapy (PTT) and photodynamic therapy (PDT) of IR780 driven by upconversion luminescence. A large number of reactive oxygen species (ROS) were generated, which led to the disintegration of the ECM and penetration into the tumors. Then, abundant Fe 3+ consumed GSH to generate ample GSSG and Fe 2+, which enhanced the sensitivity of tumor cells to oxidative stress, thus leading to the accumulation of lipid peroxide (LPO) and finally inducing ferroptosis. At the same time, substantial H 2 O 2 and Fe 2+ triggered off the Fenton-like reaction, releasing affluent free radicals. Beyond that, PTT of IR780 further promoted the Fenton-like reaction, and the generation of ROS was amplified. Free radicals generated in the process of ferroptosis destroyed heat shock protein produced by PTT, which solved the self-protection of cancer cells against heat. In situ ROS generation by the PTT/PDT of IR780 and the Fe 2+ Fenton-like reaction further promoted the accumulation of LPO and ferroptosis as well as deep penetration, which maximized the effect of combination treatment and achieved a high tumor inhibition rate (84.71%). Also, there was negligible damage to normal tissues with good tumor targeting and digestive metabolism.