Targeted Macrophage CRISPR‐Cas13 mRNA Editing in Immunotherapy for Tendon Injury

Abstract

CRISPR‐Cas13 holds substantial promise for tissue repair through its RNA editing capabilities and swift catabolism. However, conventional delivery methods fall short in addressing the heightened inflammatory response orchestrated by macrophages during the acute stages of tendon injury. In this investigation, macrophage‐targeting cationic polymers are systematically screened to facilitate the entry of Cas13 ribonucleic‐protein complex (Cas13 RNP) into macrophages. Notably, SPP1 (OPN encoding)‐producing macrophages are recognized as a profibrotic subtype that emerges during the inflammatory stage. By employing ROS‐responsive release mechanisms tailored for macrophage‐targeted Cas13 RNP editing systems, the overactivation of SPP1 is curbed in the face of an acute immune microenvironment. Upon encapsulating this composite membrane around the tendon injury site, the macrophage‐targeted Cas13 RNP effectively curtails the emergence of injury‐induced SPP1‐producing macrophages in the acute phase, leading to diminished fibroblast activation and mitigated peritendinous adhesion. Consequently, this study furnishes a swift RNA editing strategy for macrophages in the inflammatory phase triggered by ROS in tendon injury, along with a pioneering macrophage‐targeted carrier proficient in delivering Cas13 into macrophages efficiently.

The role of macrophage polarization in tendon healing and therapeutic strategies: Insights from animal models

“…( Kapur et al, 2019 ). Wang et al ( Wang et al, 2024 ) further reveal that elevated SPP1 expression in macrophages enhanced fibroblasts activation to myofibroblasts through CD44 positive feedback pathway, which indicates a crucial cascade amplification between macrophages and myofibroblasts in the field of in inflammatory hyperplasia.…”

Nanomaterials in modulating tumor-associated macrophages and enhancing immunotherapy

“…As research on miRNA and siRNA continues to progress, scientists are increasingly directing their attention to other types of RNAs, such as mRNA or lncRNA. 96 These RNAs are typically involved in modulating the immune microenvironment in the Reproduced with permission. 92 Copyright 2022, Elsevier.…”

“…As research on miRNA and siRNA continues to progress, scientists are increasingly directing their attention to other types of RNAs, such as mRNA or lncRNA. 96 These RNAs are typically involved in modulating the immune microenvironment in the form of exosomes, serving as the native RNAs of organisms. They play a significant role in regulating the polarization process of macrophages by participating in the key nodes of the polarization pathway.…”