PMID- 36055610 OWN - NLM STAT- MEDLINE DCOM- 20221018 LR - 20221123 IS - 1878-7568 (Electronic) IS - 1742-7061 (Linking) VI - 152 DP - 2022 Oct 15 TI - Macrophage membrane-camouflaged lipoprotein nanoparticles for effective obesity treatment based on a sustainable self-reinforcement strategy. PG - 519-531 LID - S1742-7061(22)00531-1 [pii] LID - 10.1016/j.actbio.2022.08.055 [doi] AB - Modern lifestyle has led to an increase in the incidence of obesity as a public health concern; however, current anti-obesity medications often show limited efficacy with severe side effects. Therapeutic drugs that are selectively delivered to adipose tissue and accelerate energy consumption are promising strategies to overcome the limitations of existing anti-obesity treatment approaches. Herein, a drug delivery platform based on a macrophage cell membrane (Ma)-camouflaged recombinant high-density lipoprotein (rHDL) that was further decorated with a P3 peptide was fabricated to realize targeted drug delivery to adipose tissue. By co-delivering rosiglitazone (Rosi), a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, and sildenafil (Sild), a phosphodiesterase type 5 (PDE5) inhibitor, a synergistic therapeutic outcome was achieved in the regulation of diet-induced obesity in a mice model. Body weight reduction and the metabolic status of obese mice were significantly improved after 28 days of treatment. More importantly, a sustainable self-reinforcement effect in multidose therapy was found after using this delivery system. The continuous treatment increased prohibitin (PHB) expression and capillary density in adipose tissue, which in turn improved the accumulation of the drugs in subsequent administration. Taken together, this constructed drug delivery system showed high effectiveness with good safety by combining two anti-obesity therapeutic agents, which exhibits promising research potential for adipose-targeted delivery. STATEMENT OF SIGNIFICANCE: Therapeutic strategies that directly target adipose tissue to increase energy consumption and regulate metabolism are promising but challenging. Herein, an adipose tissue-targeted delivery system was developed using a reconstituted high-density lipoprotein (rHDL) coated by a P3 peptide-decorated macrophage membrane. For the first time, we combined rosiglitazone (Rosi) and sildenafil (Sild) in the system and achieved synergy of adipose browning and angiogenesis for anti-obesity treatment. The therapy induced prohibitin expression and angiogenesis, which improved drug accumulation in adipose tissue in subsequent administrations. This resulted in a sustainable self-reinforcement effect with improved capacity for diet-induced obesity regulation. This study highlights the combination of adipose browning and angiogenesis in anti-obesity treatment and provides an innovative concept of enhancing adipose-targeted delivery. CI - Copyright (c) 2022. Published by Elsevier Ltd. FAU - Su, Yujie AU - Su Y AD - State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; NMPA Key laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, 99210, USA. FAU - Wang, Wei AU - Wang W AD - State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; NMPA Key laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing 210009, China. Electronic address: wangcpu209@cpu.edu.cn. FAU - Xiao, Qiaqia AU - Xiao Q AD - State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; NMPA Key laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing 210009, China. FAU - Tang, Lu AU - Tang L AD - State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; NMPA Key laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing 210009, China. FAU - Wang, Tingting AU - Wang T AD - State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; NMPA Key laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing 210009, China. FAU - Xie, Mengying AU - Xie M AD - State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; NMPA Key laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing 210009, China. FAU - Su, Yangnan AU - Su Y AD - State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; NMPA Key laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing 210009, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220830 PL - England TA - Acta Biomater JT - Acta biomaterialia JID - 101233144 RN - 0 (Hypoglycemic Agents) RN - 0 (Lipoproteins) RN - 0 (Lipoproteins, HDL) RN - 0 (Peroxisome Proliferator-Activated Receptors) RN - 05V02F2KDG (Rosiglitazone) RN - BW9B0ZE037 (Sildenafil Citrate) RN - EC 3.1.4.35 (Cyclic Nucleotide Phosphodiesterases, Type 5) SB - IM MH - Animals MH - Cyclic Nucleotide Phosphodiesterases, Type 5/therapeutic use MH - Hypoglycemic Agents/therapeutic use MH - Lipoproteins MH - Lipoproteins, HDL MH - Macrophages/metabolism MH - Mice MH - Mice, Inbred C57BL MH - Mice, Obese MH - *Nanoparticles/therapeutic use MH - Obesity/drug therapy MH - *Peroxisome Proliferator-Activated Receptors/therapeutic use MH - Rosiglitazone/therapeutic use MH - Sildenafil Citrate/therapeutic use MH - Treatment Outcome OTO - NOTNLM OT - Adipose browning OT - Angiogenesis OT - Diet-induced obesity regulation OT - Drug combination OT - Sustainable self-reinforcement effect COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/09/03 06:00 MHDA- 2022/10/19 06:00 CRDT- 2022/09/02 19:27 PHST- 2022/04/23 00:00 [received] PHST- 2022/07/14 00:00 [revised] PHST- 2022/08/23 00:00 [accepted] PHST- 2022/09/03 06:00 [pubmed] PHST- 2022/10/19 06:00 [medline] PHST- 2022/09/02 19:27 [entrez] AID - S1742-7061(22)00531-1 [pii] AID - 10.1016/j.actbio.2022.08.055 [doi] PST - ppublish SO - Acta Biomater. 2022 Oct 15;152:519-531. doi: 10.1016/j.actbio.2022.08.055. Epub 2022 Aug 30.