Engineered mesenchymal stem cells regulate integrated stress response for fibrosis therapy.

BACKGROUND: Pulmonary fibrosis is a fatal disease with limited therapeutic options. Aberrant activation of the integrated stress response (ISR) disrupts proteostasis and promotes fibrogenesis, yet effective strategies for targeted ISR regulation in fibrotic diseases remain insufficiently explored. METHODS: Here, we engineered mesenchymal stem cells (MSCs) as living carriers for targeted co-delivery of ISRIB and nicotinamide mononucleotide (NMN). ISRIB- and NMN-loaded liposomes were conjugated onto MSCs through cleavable linkers (M-Lip@IN), enabling MSC-mediated homing and microenvironment-responsive cargo release in fibrotic lesions. FINDINGS: M-Lip@IN effectively accumulated in fibrotic lungs and promoted local liposome release. ISRIB directly regulated pathological ISR activation, whereas NMN supported NAD(H)-SIRT1-related metabolic homeostasis, collectively enabling coordinated regulation of epithelial stress responses. Augmented by MSC-mediated biological support, M-Lip@IN reduced collagen deposition, inhibited profibrotic signaling, improved epithelial cell composition, promoted lung repair, and ameliorated bleomycin-induced pulmonary fibrosis, with additional antifibrotic effects observed in carbon-tetrachloride-induced liver fibrosis. CONCLUSIONS: Our study presents an engineered MSC-based platform that integrates lesion targeting, responsive drug release, and coordinated regulation of epithelial stress responses. By combining ISR modulation with metabolic resilience, M-Lip@IN restores stress homeostasis, improves epithelial cell composition, and promotes lung repair. These findings support targeted ISR regulation as a potential therapeutic strategy for pulmonary fibrosis and other fibrotic diseases. FUNDING: This work was supported by the Shenzhen Science and Technology Program, the Guangdong Basic and Applied Basic Research Foundation, the National Natural Science Foundation of China, the University Development Research Start-up Fund, and the Pengcheng Peacock Project Special Fund.