Puerarin-loaded injectable hydrogel mitigates skeletal muscle wasting in colorectal cancer cachexia by targeting inflammatory signaling and improving protein homeostasis.

Cancer cachexia (CC) is a complex, tumor-induced metabolic syndrome characterized by progressive skeletal muscle atrophy, systemic inflammation, and refractoriness to nutritional intervention, contributing to functional decline and increased mortality. Effective targeting of CC-induced skeletal muscle atrophy are major challenges in clinical treatment. Systemic administration of puerarin (PUE) is limited by poor oral bioavailability, rapid clearance, and lack of tissue-targeting capability, resulting in suboptimal therapeutic concentrations at the affected muscle tissue. This study aimed to construct a multifunctional drug delivery system: PUE was added to the oxidized dextran (OD) solution and then mixed with the phenylboronic acid (PBA)-modified carboxymethyl chitosan (CMCS-PBA) solution to form the CPO/PUE hydrogel.​ This injectable hydrogel overcomes the limitations of systemic PUE delivery by enabling sustained local release directly at the target muscle tissue, thereby enhancing therapeutic efficacy while minimizing systemic exposure. Both in vitro and in vivo experiments confirmed that the constructed CPO/PUE exhibited excellent targeting ability, significant anti-inflammatory effects, strong antioxidant activity, and pro-angiogenic effects. Experimental analysis showed that the CPO/PUE hydrogel could achieve sustained release of PUE, regulate the expression of muscle apoptosis-related proteins, inhibit the activation of the JAK2-STAT3 and NF-κB inflammatory pathways, and alleviate the suppression of the AKT-mTOR pathway. This delivery system effectively mitigates local muscle atrophy at the injection site in cancer cachexia, demonstrating a highly promising and significant therapeutic strategy.