An elastase-responsive "plug-and-play" quercetin-loaded engineered extracellular vesicle platform anchored with...

Severe acute pancreatitis (SAP) is a lethal inflammatory disease driven by a severely disregulated redox state, in which Peroxiredoxin 1 (PRDX1) acts as a key but paradoxical regulator. PRDX1 is a protective intracellular antioxidant, however, it acts as a pro-inflammatory DAMP extracellularly. To address this, we developed a "plug-and-play" therapeutic platform. Considering the microenvironment in SAP, we first engineered HEK-293 T cells to overexpress a CD63-Z domain fusion protein, yielding extracellular vesicles (EVs) capable of high-affinity binding to the Fc region of various antibodies. We then armed these EVs with an anti-PRDX1 antibody via an elastase-responsive linker and co-loaded them with quercetin (Ab-Fc-EL-EV@Que). After active pancreatic targeting, locally concentrated elastase triggered antibody release from the Ab-Fc-EL-EV@Que. to neutralize extracellular PRDX1, which has been confirmed to activate the TLR/NF-κB pathway in macrophages, thereby suppressing the inflammatory cascade. Subsequently, the antibody-detached EVs were internalized by acinar cells, delivering Que. to promote intracellular PRDX1 acetylation, enhance antioxidant capacity, and ultimately protect acinar cells from ferroptosis and apoptosis. This work not only offers a potent, multi-mechanistic modality for SAP by resolving the PRDX1 paradox but also establishes a highly adaptable "plug-and-play" platform for tailored therapies against other complex diseases.