Bioinspired plant-derived extracellular vesicles enabling dual-targeting therapy for primary ovarian insufficiency.

Abstract

Extracellular vesicles (EVs) have emerged as promising therapeutic agents for restoring ovarian function and fertility in chemotherapy-induced premature ovarian insufficiency (POI). However, their limited ovarian targeting capacity and inefficient mitochondrial delivery have substantially constrained their therapeutic efficacy. Here, we present a biomimetic, dual-targeted EV platform derived from Lycium barbarum (TPP-GCM-LBEVs) and demonstrate its therapeutic potential in a mouse POI model. Hybridization with granulosa cell membranes (GCMs) confers intrinsic ovarian-homing capability, whereas subsequent surface conjugation with triphenylphosphonium (TPP) promotes mitochondrial targeting following cellular uptake. TPP-GCM-LBEVs efficiently target granulosa cells and their mitochondria in vitro and in vivo, with cellular internalization mediated predominantly by caveolae- and lipid-raft-dependent endocytosis. Subsequently, TPP-GCM-LBEVs restore mitochondrial ultrastructure and bioenergetic function in granulosa cells, thereby re-establishing ovarian redox and metabolic homeostasis. This mitochondrial rescue enhances the paracrine metabolic support provided to oocytes, thereby improving oocyte quality and developmental competence. Consistent with these effects, treatment with TPP-GCM-LBEVs rescues follicular development, ovarian endocrine function, and natural fertility in POI mice. Collectively, this cross-species, dual-targeted, plant-derived EV strategy provides a translatable and effective therapeutic framework for POI, with broader implications for mitochondria-associated reproductive ageing.