Work

A multifunctional hydrogel for obesity-associated tumor immunotherapy and postsurgical wound healing promotion

Year: 2025

Type: article

Abstract: The multidimensional complexity between metabolism and inflammation within the obese tumor microenvironment (OTME) poses substantial barriers to postsurgical immunotherapy and wound management. Herein, we engineered a multifunctional hydrogel (Lipo/CXB@Hydrogel) through covalent conjugation of dopamine-crosslinked oxidized hyaluronic acid and a ROS-sensitive linker, co-delivering the non-steroidal anti-inflammatory drug celecoxib (CXB) and the lipid metabolism modulator Lipofermata (Lipo) to facilitate T cell immunotherapy and wound healing. The unique multi-dynamic-bond crosslinked structure endows the hydrogel with excellent self-healing, tissue adhesiveness and mechanical properties. The implanted Lipo/CXB@Hydrogel degrades and releases CXB to suppress hyperinflammation and enhance intratumoral cytotoxic T lymphocyte (CTL) infiltration, while Lipo inhibits the predatory uptake of fatty acids by tumor cells in the OTME for competing metabolic resources of intratumoral infiltrated CTLs. Importantly, such a cascaded immunological effect of Lipo/CXB@Hydrogel treatment amplifies CTL proliferation and activity specifically through targeting the arachidonic acid (AA)/COX-2/PGE2 signaling axis, a central hub linking lipid metabolism and inflammation, initiating a long-lasting immune response to suppress colorectal tumor postsurgical recurrence and metastasis in obesity contexts. Moreover, the hydrogel can easily repeatedly close the reopened wounds and promote skin regeneration. Thus, this multifunctional hydrogel may provide a promising strategy for postsurgical obese tumor immunotherapy and wound closure. • Multifunctional Hydrogel Platform: A multi-dynamic-bond crosslinked hydrogel (Lipo/CXB@Hydrogel) offers excellent self-healing, tissue adhesion, mechanical stability, and tunable degradation for post-surgical application. • Sustained Release & Improved Delivery: Single in-situ implantation provides precise, prolonged CXB release (extending duration from 4 h to 2 weeks), overcoming limitations of frequent dosing and monotherapy resistance. • Synergistic Immuno-Metabolic Therapy: Releases CXB to suppress inflammation and enhance CTL infiltration, while Lipo blocks tumor fatty acid uptake in OTME, synergistically amplifying CTL activation via targeting the AA/COX-2/PGE2 axis to prevent recurrence. • Integrated Wound Management: The hydrogel simultaneously promotes skin regeneration and effectively seals reopened wounds, addressing post-surgical healing challenges.

Source: Bioactive Materials

DOI: 10.1016/j.bioactmat.2025.11.027