Synergistic anti-obesity therapy: ursolic acid-loaded mesoporous polydopamine nanoparticles (MPDA@UA) in an injectable OHA-CMCS hydrogel with a mild photothermal effect for adipocyte reprogramming

Obesity and its metabolic complications urgently require safe, effective, and minimally invasive interventions. Here, we engineered an injectable, self-healing hydrogel system (OCMU hydrogel) based on oxidized hyaluronic acid (OHA) and carboxymethyl chitosan (CMCS) for the localized delivery of plant-based ursolic acid (UA) loaded in mesoporous polydopamine (MPDA) nanoparticles. This system synergistically induces white adipose browning through combined photothermal therapy (PTT) and pharmacological action, effectively counteracting obesity. The OCMU hydrogel exhibited excellent self-healing properties, high UA loading capacity (81.04%), efficient photothermal conversion, and favorable biocompatibility. Mechanistically, the system promotes lipolysis, mitochondrial biogenesis, and adipose browning via activation of the AMPK/SIRT1/PGC-1α pathway, with a 439% increase in UCP1 expression in vitro. In obese mice, OCMU combined with PTT reduced body weight by 10.94% and inguinal fat by 56.32%, while significantly improving metabolic profiles and alleviating inflammation. Notably, the combination of mild PTT and naturally derived UA achieved superior anti-obesity efficacy compared to monotherapies, highlighting a favorable safety and efficacy profile. This work establishes a promising platform in which UA and mild PTT act in concert to reprogram adipocyte metabolism, offering a safe and synergistic approach to combat obesity.