Interleukin-10 plasmid delivery by polymeric nanocarrier shows efficient and safe tissue repair in acute muscle damage models in mice

We established a custom-designed nanocarrier for in vivo delivery of an immunomodulatory plasmid capable of facilitating tissue repair in acute muscle damage models in mice. The nanocarrier was con-structed by selecting from versatile cationic designs that were used to complex with a negatively charged plasmid, while the excessive positive charge was shielded by the poly (glutamic acid)-polyethylene glycol co-polymer. The best-performing formulation was identified by high throughput screening in macrophages, in which we obtained the hierarchical ranking in terms of reporter gene expression (GFP plasmid, pGFP) and macrophage polarization status (interleukin 10 plasmid, pIL-10). For proof-of-principle, we performed in-tramuscular (IM) injection of pGFP nanocarrier in a cardiotoxin-induced muscle injury model. After con-firming the in vivo GFP transfection, we demonstrated protected delivery of pIL-10 to the injured muscle site, leading to an accelerated tissue repair outcome. Immunophenotyping analysis revealed the increased number of M2 macrophages and regulatory T cells, as well as increased IL-10 production at muscle site. The effectiveness of the pIL-10 carrier was interfered by pharmaceutical macrophage depletion using pre -in-jected clodronate liposome. When intravenously (IV) injected, our pIL-10 nanocarrier preferentially bio-distributed in the injured muscle (owing to transiently decreased blood vessel integrity) and improved tissue repair. Unlike IL-10 protein (that was clinically abandoned), sustained IL-10 production by our na-nocarrier dramatically reduced the degree of spleen enlargement and kidney inflammation, suggesting a favorable safety characteristic in vivo. (c) 2022 Published by Elsevier Ltd.

Automated summary

We developed a custom-designed nanocarrier for delivering an immunomodulatory plasmid in mice to facilitate tissue repair in acute muscle damage. Through high throughput screening, we identified the best-performing formulation and demonstrated successful delivery of the plasmid to the injured muscle, resulting in accelerated tissue repair. This study highlights the potential of nanocarriers in treating muscle injuries.