Labeling Assembly of Hydrophilic Methionine into Nanoparticle for Mild‐Heat Mediated Immunometabolic Therapy

Abstract Methionine metabolism has a significant impact on T cells’ survival and activation even in comparison to arginine, a well‐documented amino acid in metabolic therapy. However, hydrophilic methionine is hardly delivered into TME due to difficult loading and rapid diffusion. Herein, the labeling assembly of methionine into nanoparticle is developed to overcome high hydrophilicity for mild‐heat mediated immunometabolic therapy. The strategy is to first label methionine with protocatechualdehyde (as the tag) via reversible Schiff‐base bond, and then drive nanoassembly of methionine (MPC@Fe) mediated by iron ions. In this fashion, a loading efficiency of 40% and assembly induced photothermal characteristics can be achieved. MPC@Fe can accumulate persistently in tumor up to 36 h due to tumor‐selective aggregation in acidic TME. A mild heat of 43 °C on tumor by light irradiation stimulated the immunogenic cell death and effectively generated CD8 + T cells. Notably, MPC@Fe assisted by mild heat promoted 4.2‐fold of tumor‐infiltrating INF‐ γ + CD8 + T cells, leading to an inhibition ratio of 27.3‐fold versus the free methionine. Such labeling assembly provides a promising methionine delivery platform to realize mild heat mediated immunometabolic therapy, and is potentially extensible to other amino acids.