Targeted peptide modification of mesenchymal stem cells enhances their therapeutic efficacy in the treatment of idiopathic pulmonary fibrosis

Zelin Lei^1*Rui Jia²Yixuan Ren²Yirun Zhao²Yun Wang³Wenqian Cao²Xue Bai¹Yali Peng²

• ¹Lanzhou University First Hospital, Lanzhou, China
• ²Lanzhou University, Lanzhou, China
• ³Gansu University of Chinese Medicine, Lanzhou, China

Background Mesenchymal Stem Cells (MSCs), derived from the mesoderm, are adult stem cells characterized by self-renewal, multipotency, and low immunogenicity, making them promising candidates for regenerative therapies. Their intrinsic capacity to migrate to sites of injury and differentiate into diverse cell types presents considerable therapeutic potential. Particularly for lung diseases such as Idiopathic Pulmonary Fibrosis (IPF)— a chronic, progressive, and fatal lung condition with limited treatment options. Despite the potential of MSCs therapy, key challenges remain, including poor homing efficiency and limited retention in target tissues, particularly after systemic administration. Current methods do not adequately address these limitations, resulting in suboptimal therapeutic outcomes in IPF treatment. Enhancing the homing and retention of MSCs in lung tissue is critical for maximizing their therapeutic efficacy, yet an effective strategy for overcoming this challenge is still lacking. Methods Here, the synthesis of SA2-PEG-Peptides and their analogs was conducted using solid-phase peptide synthesis (SPPS). Two distinct strategies were devised: the first based on metabolic glycoengineering with in vivo bioorthogonal copper-free click chemistry to modify functional molecules on the MSCs surface, and the second involving phospholipid-polyethylene glycol modification of MSCs, coupling lung-targeted peptides with phospholipids for surface modification. The efficacy of these strategies was evaluated by examining retention time on the cell membrane, cell viability, cytotoxicity, membrane integrity, hemolysis, and drug distribution in mice. Results While the Metabolic Glycoengineering (MGE) approach did not achieve the desired modification results, the co-modification strategy using SA2-PEG2000 and SA2-PEG2000-CAR significantly enhanced the homing and retention of MSCs in lung tissue. This modification also substantially improved the therapeutic efficacy of MSCs in treating IPF. Conclusion In this study, we developed a cellular modification strategy based on SA2-PEG-Peptides and PEGylation. Co-modifying MSCs with SA2-PEG2000 and SA2-PEG2000-CAR markedly improved their lung-targeting and retention capacity, resulting in enhanced therapeutic outcomes for IPF. This strategy offers a potential pathway for optimizing MSCs therapies for lung diseases and may be applied to enhance the efficacy of stem cell therapies across a variety of conditions.