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 NH4F/NaOH, we developed NaTmF4:0.5%Er3+@NaLuF4 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 H2O2, 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 Fe3+ consumed GSH to generate ample GSSG and Fe2+,
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 H2O2 and Fe2+ 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 Fe2+ 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.