Adipose tissue targeted sequential delivery system regulating glycolipid metabolism for systemic obesity and its comorbidities

Obesity has emerged as a chronic, relapsing, progressive disease globally. Available methods including pharmacotherapy, surgery, and limotherapy, may lead to toxicities and gastrointestinal disturbances due to their lack of adipose tissue targetability. Increasing energy expenditure and reducing gluconeogenesis through browning of white adipose tissue (WAT) is a therapeutic target for obesity and its comorbidities. Here, we constructed a biomimetic discoidal recombinant high-density lipoprotein (rHDL) with high specificity for scavenger receptor class B type I (SR-BI). rHDL enables targeted delivery of combination drugs (RM) containing rosiglitazone (Rosi) and metformin (Met) to WAT, liver, and intestine, that express elevated levels of SR-BI, resulting in promoted browning of WAT, enhanced mitochondrial biogenesis, and adipocyte thermogenesis increase. For oral delivery, rHDL@RM was loaded in pH-senstive sodium alginate chitosan complex microspheres (MS), enabling stepwise release in the gastrointestinal tract, with mucosal penetration capability that facilitating longlasting lipid-lowering effect. Diet-induced obese (DIO) mice treated with rHDL@RM/MS showed 44.6 % reduction in body weight, with decreased serum glucose and lipid levels. Obesity comorbidities, including NAFLD, gut microbiome disorders, systemic lipid metabolism abnormalities, and chronic inflammation, were all effectively suppressed. Our designed rHDL@RM/MS oral-nanoplatform represents a valuable therapeutic strategy for painless treatment of systemic obesity and related comorbidities. [Display omitted] •High targeting specificity for the SR-BI receptor and promotion of WAT-to-BAT conversion.•Lipid-lowering and blood glucose control with glycolipid metabolism regulation in vivo.•The management of obesity-related comorbidities, including NAFLD, steatohepatitis, gut microbiota dysbiosis, and inflammation.