Photothermally amplified NO release from arginine-encapsulated injectable nanocomposite hydrogel for triple-synergistic antitumor therapy

Monotherapeutics remain constrained by adaptive resistance mechanisms and inherent limitations imposed by tumor evolutionary pressure. Here, an injectable natural material-based hydrogel HC&Arg&Au/D was constructed to achieve multi-strategy combined anti-tumor therapy. Tyrosine-grafted hyaluronic acid (HA) achieved horseradish peroxidase (HRP)-catalyzed covalent crosslinking. 3-aminophenylboronic acid-modified carboxymethyl cellulose (CMC) formed pH-sensitive boronic ester bonds with HA's cis-diol groups, enabling acid-triggered degradation and drug release. Then, HC&Arg&Au/D hydrogel stably formed after subcutaneous implantation and safely degraded within three weeks, enabling sustained drug release at the tumor site. Specifically, doxorubicin (Dox) and gold nanoparticle (AuNP)-mediated photothermal therapy (PTT) synergistically induced tumor cell apoptosis and triggered immunogenic cell death (ICD). L-arginine (Arg) modulated the pH of the tumor microenvironment (TME), promoting the recruitment and polarization of M1 macrophages. Furthermore, the Arg/Au-containing hydrogel produced an NO assay signal under PTT and was associated with downregulation of the membrane transporter SLC7A11 and lipid peroxide accumulation. Because GPX4 protein abundance was unchanged, these findings support an additional redox contribution but do not by themselves establish canonical ferroptosis. These tightly coordinated therapeutic strategies collectively achieved remarkable anti-tumor efficacy, resulting in complete ablation of 4T1 orthotopic tumors in 40% of treated mice and significant volume reduction in remaining mice. This spatiotemporally controllable multimodal therapy system provides a basis for further study of functionalized hydrogel carriers that combine PTT, chemotherapy and immune modulation.