Viscoelastic hydrogel primed CAR-macrophage for pulmonary fibrosis treatment.

CAR-macrophage (CAR-M) therapy holds promise for the treatment of tumor and fibrotic diseases, yet genetic engineering remains the main efficacy-enhancing approach. Here we develop a non-genetic strategy using viscoelastic hydrogel to mechanically prime CAR-Ms. CAR-Ms exhibit potent phagocytosis of activated fibroblasts and collagen-degradation capacity, and hydrogel priming further enhances their cytotoxicity. Mechanistically, viscoelastic hydrogel priming reduces CAR-M membrane tension, which triggers membrane CAR to disassemble from clusters into dispersed monomers and dimers, leading to enhanced downstream signaling. In pulmonary fibrosis models, hydrogel-primed CAR-Ms demonstrate superior therapeutic outcomes, showing fibrosis reduction and microenvironment improvement. This study highlights CAR-M therapy's potential for pulmonary fibrosis treatment and offers a distinct approach to improve CAR-M efficacy by physical stimuli.