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

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 synd...

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Bibliographic Details
Published in:Advanced materials (Weinheim) 2024-04, Vol.36 (16), p.e2309920-n/a
Main Authors: Choi, Heekyung, Hong, Juhyeong, Seo, Yuha, Joo, Seung‐Hwan, Lim, Hanseok, Lahiji, Shayan Fakhraei, Kim, Yong‐Hee
Format: Article
Language:English
Subjects:
adipocyte targeting anti‐obesity gene knockdown
Adipocytes
Adipose tissue
Administration, Cutaneous
Animals
Body weight
Diabetes Mellitus, Type 2 - drug therapy
dissolving microneedle
Drug Delivery Systems
dual shRNA
Effectiveness
Gene therapy
Genetic Therapy
Humans
Hyaluronic acid
Infectious diseases
Metabolic disorders
Metabolism
Mice
Needles
Obesity
Obesity - drug therapy
oligopeptoplexes
Self-assembly
Storage stability
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Summary: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. Dissolvable hyaluronic acid‐based self‐locking microneedle patch loaded with self‐assembled oligopeptoplex optimized for targeted delivery of FABPs‐silencing shRNA to obese adipocytes represents significant FABPs downregulation in adipose tissue, reduction in body weight, and amelioration of insulin resistance, potentiating it as a novel transdermal gene delivery platform for obesity and obesity‐induced metabolic syndrome.
ISSN:0935-9648
1521-4095
DOI:10.1002/adma.202309920