Self‐Assembled Oligopeptoplex‐Loaded Dissolving Microneedles for Adipocyte‐Targeted Anti‐Obesity Gene Therapy

Abstract Advancements in gene delivery systems are pivotal for gene‐based therapeutics in oncological, inflammatory, and infectious diseases. This study delineates the design of a self‐assembled oligopeptoplex (SA‐OP) optimized for shRNA delivery to adipocytes, targeting obesity and associated metabolic syndromes. Conventional systems face challenges, including instability due to electrostatic interactions between genetic materials and cationic oligopeptides. Additionally, repeated injections induce discomfort and compromise patient well‐being. To circumvent these issues, a dissolvable hyaluronic acid‐based, self‐locking microneedle (LMN) patch is developed, with improved micro‐dose efficiency, for precise SA‐OP delivery. This platform offers pain‐free administration and improved SA‐OP storage stability. In vitro studies in 3T3‐L1 cells demonstrated improvements in SA‐OP preservation and gene silencing efficacy. In vivo evaluation in a mice model of diet‐induced type 2 diabetes yielded significant gene silencing in adipose tissue and a 21.92 ± 2.51% reduction in body weight with minimum relapse risk at 6‐weeks post‐treatment, representing a superior therapeutic efficacy in a truncated timeframe relative to the GLP‐1 analogues currently available on the market. Additionally, SA‐OP (LMN) mitigated insulin resistance, inflammation, and hepatic steatosis. These findings establish SA‐OP (LMN) as a robust, minimally invasive transdermal gene delivery platform with prolonged storage stability for treating obesity and its metabolic comorbidities.