Selective Lipolysis by Photoactivation of Chaperone‐Mediated Autophagy Using Adipocyte Membrane‐Coated Nanoparticle in Hydrogel

Abstract Despite the clinical importance of obesity, treatments have been confined to surgery or drugs, both of which carry adverse effects. Herein a nanomaterial consisting of adipocyte membrane‐coated and rosiglitazone‐loaded polydopamine nanoparticles embedded in hydrogel (ARNP‐H) is designed aiming to induce selective lipolysis in adipocyte through activation of chaperone‐mediated autophagy (CMA) by mild photothermal heat stress. Adipocyte membrane‐coated and rosiglitazone‐loaded polydopamine nanoparticles (ARNP) are taken up by adipocyte to a significantly greater extent than other cell membrane‐coated nanoparticles. Adipocyte interactions with ARNP are significantly higher than those with other cells such as macrophages and T cells. ARNP‐H enabled selective activation of CMA in adipocytes, increasing levels of heat shock cognate protein 70, a key component of CMA. Colocalization of heat shock cognate protein 70 and breakdown of CMA substrate perilipin 2, led to enhancement of adipose triglyceride lipase access to lipid droplets, initiating lipolysis. In high‐fat diet‐fed mice, ARNP‐H retention at the local injection site is greater than in other groups, maintaining photothermal responsiveness for over 3 days. ARNP‐H treatment significantly enhanced adipocyte lipolysis and led to substantial weight loss. While this study focuses on obesity model, ARNP‐H for CMA photoactivation holds potential for treating other diseases associated with autophagy dysregulation.