Targeted Elimination of FAP⁺ Fibroblasts by BiTE-Engineered Extracellular Vesicles Prevents Epidural Fibrosis

Epidural fibrosis (EF) is a frequent and debilitating complication that impairs recovery following spinal surgery, yet effective targeted therapies are lacking. Here we observe enrichment of FAP⁺ fibroblasts at surgical sites in patients after laminectomy. To therapeutically target this subset, we develop bispecific antibody–decorated extracellular vesicles (BsAb EVs), which redirect endogenous T cells to eliminate FAP⁺ fibroblasts in situ. In a preclinical model, BsAb EVs selectively eliminate pathogenic fibroblasts, reduce fibrotic collagen accumulation, and prevent the development of postoperative epidural fibrosis without detectable systemic toxicity under the tested conditions. Single-cell RNA sequencing reveals that FAP⁺ fibroblasts represent a transcriptionally distinct subset from α-SMA⁺ myofibroblasts, characterized by enhanced extracellular matrix remodeling and TGF-β production. Together, these findings highlight a critical stromal subset in EF pathogenesis and position BsAb EVs as a promising immunotherapeutic strategy for targeting pathogenic stromal cells in fibrotic and tissue-remodeling disorders.