PMID- 38272900 OWN - NLM STAT- MEDLINE DCOM- 20240129 LR - 20240206 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 15 IP - 1 DP - 2024 Jan 25 TI - LNP-RNA-engineered adipose stem cells for accelerated diabetic wound healing. PG - 739 LID - 10.1038/s41467-024-45094-5 [doi] LID - 739 AB - Adipose stem cells (ASCs) have attracted considerable attention as potential therapeutic agents due to their ability to promote tissue regeneration. However, their limited tissue repair capability has posed a challenge in achieving optimal therapeutic outcomes. Herein, we conceive a series of lipid nanoparticles to reprogram ASCs with durable protein secretion capacity for enhanced tissue engineering and regeneration. In vitro studies identify that the isomannide-derived lipid nanoparticles (DIM1T LNP) efficiently deliver RNAs to ASCs. Co-delivery of self-amplifying RNA (saRNA) and E3 mRNA complex (the combination of saRNA and E3 mRNA is named SEC) using DIM1T LNP modulates host immune responses against saRNAs and facilitates the durable production of proteins of interest in ASCs. The DIM1T LNP-SEC engineered ASCs (DS-ASCs) prolong expression of hepatocyte growth factor (HGF) and C-X-C motif chemokine ligand 12 (CXCL12), which show superior wound healing efficacy over their wild-type and DIM1T LNP-mRNA counterparts in the diabetic cutaneous wound model. Overall, this work suggests LNPs as an effective platform to engineer ASCs with enhanced protein generation ability, expediting the development of ASCs-based cell therapies. CI - (c) 2024. The Author(s). FAU - Xue, Yonger AU - Xue Y AUID- ORCID: 0000-0002-6022-2487 AD - Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA. AD - Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Zhang, Yuebao AU - Zhang Y AUID- ORCID: 0009-0000-7883-1937 AD - Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA. FAU - Zhong, Yichen AU - Zhong Y AD - Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA. AD - Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Du, Shi AU - Du S AD - Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA. FAU - Hou, Xucheng AU - Hou X AD - Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Li, Wenqing AU - Li W AD - Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA. FAU - Li, Haoyuan AU - Li H AD - Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Wang, Siyu AU - Wang S AD - Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Wang, Chang AU - Wang C AD - Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Yan, Jingyue AU - Yan J AD - Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA. FAU - Kang, Diana D AU - Kang DD AD - Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA. FAU - Deng, Binbin AU - Deng B AD - Center for Electron Microscopy and Analysis, The Ohio State University, Columbus, OH, USA. FAU - McComb, David W AU - McComb DW AUID- ORCID: 0000-0003-3763-9652 AD - Center for Electron Microscopy and Analysis, The Ohio State University, Columbus, OH, USA. AD - Department of Materials Science and Engineering, The Ohio State University, Columbus, OH, USA. FAU - Irvine, Darrell J AU - Irvine DJ AUID- ORCID: 0000-0002-8637-1405 AD - Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. AD - Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. AD - Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. AD - Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. AD - Howard Hughes Medical Institute, Chevy Chase, MD, USA. FAU - Weiss, Ron AU - Weiss R AUID- ORCID: 0000-0003-0396-2443 AD - Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. AD - Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. AD - Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. FAU - Dong, Yizhou AU - Dong Y AUID- ORCID: 0000-0001-5786-0659 AD - Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA. yizhou.dong@mssm.edu. AD - Icahn Genomics Institute, Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Oncological Sciences, Tisch Cancer Institute, Friedman Brain Institute, Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. yizhou.dong@mssm.edu. LA - eng GR - R35 GM119679/GM/NIGMS NIH HHS/United States GR - R35 GM144117/GM/NIGMS NIH HHS/United States PT - Journal Article DEP - 20240125 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 RN - 63231-63-0 (RNA) RN - 0 (RNA, Messenger) SB - IM MH - Humans MH - *Adipose Tissue/metabolism MH - RNA/metabolism MH - Wound Healing/genetics MH - RNA, Messenger/genetics/metabolism MH - Stem Cells/metabolism MH - *Diabetes Mellitus/metabolism PMC - PMC10811230 COIS- Y.X., Y.Zhang., D.J.I., R.W., and Y.D. are inventors on a patent application (63/433,109) filed by The Ohio State University and Massachusetts Institute of Technology. The patent covers engineered ASCs and their uses in this work. Y.D. is a scientific advisory board member and holds equity in Arbor Biotechnologies and Sirnagen Therapeutics. Y.D. is a co-founder and holds equity in Immunanoengineering Therapeutics. D.J.I. and R.W. are scientific advisory board members and hold equity in Strand Therapeutics. Other authors declare no conflict of interest. EDAT- 2024/01/26 00:43 MHDA- 2024/01/29 06:44 PMCR- 2024/01/25 CRDT- 2024/01/25 23:15 PHST- 2023/05/07 00:00 [received] PHST- 2024/01/15 00:00 [accepted] PHST- 2024/01/29 06:44 [medline] PHST- 2024/01/26 00:43 [pubmed] PHST- 2024/01/25 23:15 [entrez] PHST- 2024/01/25 00:00 [pmc-release] AID - 10.1038/s41467-024-45094-5 [pii] AID - 45094 [pii] AID - 10.1038/s41467-024-45094-5 [doi] PST - epublish SO - Nat Commun. 2024 Jan 25;15(1):739. doi: 10.1038/s41467-024-45094-5.