Adipocyte-targeted celastrol delivery biguanide-modified micelles improves treatment of obesity in DIO mice.

Obesity has emerged as a significant global health burden, exacerbated by serious side effects associated with existing anti-obesity medications. Celastrol (CLT) holds promise for weight loss but encounters challenges related to poor solubility and systemic toxicity. Here, we present chondroitin sulfate (CS)-derived micelles engineered for adipocyte-specific targeting, aiming to enhance the therapeutic potential of CLT while minimizing its systemic toxicity. To further enhance adipocyte affinity, we introduced a biguanide moiety into a micellar vehicle. CS is sequentially modified with hydrophilic metformin and hydrophobic 4-aminophenylboronic acid pinacol ester (PBE), resulting in the self-assembly of CLT-encapsulated micelles (MET-CS-PBE@CLT). This innovative design imparts amphiphilicity the PBE moieties while ensuring the outward exposure of hydrophilic metformin moieties, facilitating active interactions with adipocytes. studies confirmed the enhanced uptake of MET-CS-PBE@CLT micelles by adipocytes, while studies demonstrated increased distribution within adipose tissues. In a diet-induced obese mouse model, MET-CS-PBE@CLT exhibited remarkable efficacy in weight loss without affecting food intake. This pioneering strategy offers a promising, low-risk, and highly effective solution to address the global obesity epidemic.