Light-driven thermotropic hydrogel with nanomodulator enables lipid intervention and cavity delivery for postsurgical tumor therapy.

Abstract

Fatty acid-rich milieu is recognized as a potential key factor driving postsurgical tumor recurrence, while insufficient drug delivery to irregular surgical margins further compromises therapeutic effects. We find that this milieu directly drives lipid droplet accumulation in tumor-associated macrophages (TAMs), promoting M2 polarization, which can be reversed by rapamycin (Ra) via enhanced lipid droplet metabolism. Accordingly, we design a light-driven thermotropic hydrogel (LTG@RL) encapsulating a nanomodulator (R@LOX) containing lipoxygenase and Ra. Upon photothermal irradiation, LTG@RL undergoes reversible gel-sol transition for deep cavity penetration and sustained retention. R@LOX coordinates lipid intervention. It uses tumor-derived fatty acids to generate lipid peroxides, inducing ferroptosis in residual cancer cells, while repolarizing TAMs to the M1 phenotype to restore immune surveillance. In postsurgical melanoma and breast cancer models, LTG@RL suppresses tumor recurrence, prolongs survival, and also exhibits activity in non-surgical melanoma models. This strategy integrates lipid intervention and enhanced cavity delivery, offering precision prevention of postsurgical recurrence.