Engineered mesenchymal stem cells regulate integrated stress response for fibrosis therapy

Area of Science:

• Biomedical Engineering
• Regenerative Medicine
• Drug Delivery Systems

Background:

• Pulmonary fibrosis is a fatal lung disease with limited treatment options.
• Aberrant integrated stress response (ISR) activation contributes to fibrogenesis.
• Targeted ISR regulation strategies for fibrotic diseases are underexplored.

Purpose of the Study:

• To develop an engineered mesenchymal stem cell (MSC) platform for targeted delivery of ISRIB and nicotinamide mononucleotide (NMN).
• To investigate the combined therapeutic effects of ISR modulation and metabolic support in fibrotic diseases.

Main Methods:

• MSCs were engineered to co-deliver ISRIB and NMN via liposomes (M-Lip@IN) attached by cleavable linkers.
• M-Lip@IN utilized MSCs for homing to fibrotic lesions and responsive cargo release.
• The therapeutic efficacy was evaluated in bleomycin-induced pulmonary fibrosis and carbon-tetrachloride-induced liver fibrosis models.

Main Results:

• M-Lip@IN effectively accumulated in fibrotic lungs, releasing its cargo locally.
• ISRIB targeted pathological ISR activation, while NMN restored metabolic homeostasis via NAD(H)-SIRT1.
• The treatment reduced collagen deposition, inhibited profibrotic signaling, improved lung epithelial cell composition, and promoted repair, also showing liver fibrosis benefits.

Conclusions:

• An engineered MSC platform (M-Lip@IN) enables targeted delivery and responsive release for fibrotic disease treatment.
• Combining ISR modulation with metabolic support restores stress homeostasis and promotes tissue repair.
• Targeted ISR regulation represents a promising therapeutic strategy for pulmonary and other fibrotic conditions.