Brain-targeted PROTAC delivery by dual-functional extracellular vesicles achieves robust LRRK2 degradation in a Parkinson’s disease model

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Abstract Mesenchymal stem cell–derived extracellular vesicles (MSC-EVs) have emerged as promising therapeutic delivery vehicles for brain diseases. However, their limited ability to cross the blood–brain barrier (BBB) remains a major obstacle to clinical translation. To overcome this limitation, we designed a multifunctional peptide consisting of a membrane-anchoring transmembrane domain (TD) and a cell-penetrating peptide (CPP) that can spontaneously insert into the EV membrane without external energy input. The brain-targeting T7 sequence was placed at the distal end to ensure directional display on the EV surface, thereby improving targeting efficiency. Using this approach, we generated T7-displaying MSC-EVs and passively loaded proteolysis-targeting chimeras (PROTACs) to enhance their therapeutic potential. The structural integrity, cellular uptake, and BBB permeability of engineered EVs were evaluated through in vitro neuronal assays and in vivo brain imaging. T7-TD-CPP EVs exhibited markedly improved cellular internalization and BBB penetration, while PROTAC co-loading facilitated degradation of pathological proteins. In an MPTP-induced Parkinson’s disease mouse model, treatment with T7-EV–PROTACs alleviated disease-associated pathology, including abnormal expression of LRRK2 in the midbrain. This EV platform, combining energy-independent membrane anchoring with T7-mediated brain targeting, represents a promising strategy for precise, brain-directed therapy against neurodegenerative diseases.

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