Nanocontroller-mediated dissolving hydrogel that can sustainably release cold-mimetic menthol to induce adipocyte browning for treating obesity and its related metabolic disorders

Abstract

Obesity leads to the development of many metabolic diseases, causing severe health problems. Menthol can induce adipocyte browning and thus has been used to combat obesity. To deliver menthol with a sustained effect, an injectable hydrogel that comprises carboxymethyl chitosan and aldehyde-functionalized alginate that are crosslinked through dynamic Schiff-base linkages is developed to load menthol-cyclodextrin inclusion complexes (IC). To render the as-developed hydrogel soluble after its payload is released, amino acid-loaded liposomes, functioning as nanocontrollers, are covalently grafted onto networks of the hydrogel. Upon subcutaneous injection in mice with diet-induced obesity, the as-developed hydrogel absorbs body fluids and spontaneously swells, expanding and stretching its networks, gradually releasing the loaded IC. Menthol then disassociates from the released IC to induce adipocyte browning, triggering fat consumption and increasing energy expenditure. Meanwhile, the expanded hydrogel networks destabilize the grafted liposomes, which function as built-in nanocontrollers, unleashing their loaded amino acid molecules to disrupt the dynamic Schiff-base linkages, causing hydrogel to dissolve. The thus-developed nanocontroller-mediated dissolving hydrogel realizes the sustained release of menthol for treating obesity and its related metabolic disorders without leaving exogenous hydrogel materials inside the body, and thereby preventing any undesired adverse effects.