Abstract

Obesity and type 2 diabetes mellitus (T2DM) are complex polygenic diseases in which environmental factors 
act on a susceptible genomic background to drive chronic energy imbalance, insulin resistance and β-cell failure. 
Although current pharmacotherapies improve glycemic control and reduce weight in many patients, they do not 
correct upstream genetic and epigenetic drivers of disease. CRISPR-based genome editing offers the possibility 
of durable modification of key metabolic pathways, including brown/beige adipocyte thermogenesis, lipid 
handling, appetite regulation and pancreatic islet function. However, safe and efficient delivery of CRISPR 
components to specific metabolic tissues remains a major bottleneck. Nanoparticle platforms like lipid 
nanoparticles, polymeric carriers, inorganic and hybrid systems are emerging as versatile vehicles for in vivo 
delivery of CRISPR ribonucleoproteins (RNPs), mRNA and base or prime editors to adipose tissue, liver, skeletal 
muscle and pancreatic islets. This review discusses the rationale for gene editing in obesity and diabetes, outlines 
priority genetic targets, and focuses on the design principles and performance of nanoparticle-based CRISPR 
delivery systems. We highlight preclinical studies that edit genes such as PCSK9, ANGPTL3, Fabp4, Ucp1 
regulators and glucoregulatory pathways to improve lipid profiles, insulin sensitivity and body weight in rodent 
models. Challenges related to tissue specificity, editing efficiency, off-target effects, immunogenicity, 
manufacturing and ethics are examined, alongside future directions including tissue-tropic nanoparticles, 
multiplex editing and combinatorial strategies with GLP-1 agonists and lifestyle interventions. By enabling 
controllable, non-viral delivery of gene editors to metabolic tissues, CRISPR–nanoparticle systems could form 
the basis of next-generation therapies for obesity-associated diabetes.