EV-delivered Acacetin and NMN rescue sperm motility and count via ferroptosis inhibition and NAD+ boost.

Asthenozoospermia, characterized by reduced sperm motility, is a major contributor to male infertility, affecting millions globally. Current treatments often lack targeted delivery, comprehensive mechanistic action, or real-time monitoring capabilities. Sperm function is highly susceptible to oxidative stress and metabolic dysfunction, with ferroptosis (a form of iron-dependent programmed cell death) and depleted NAD+ levels emerging as critical pathways impacting sperm viability and motility. Addressing these intertwined issues simultaneously with a traceable therapeutic platform represents a significant unmet need in reproductive medicine.

Researchers developed a novel "AIE-Pharmacology" approach using the natural flavonoid acacetin as an intrinsic aggregation-induced emission (AIE) luminogen with therapeutic properties. They engineered an extracellular vesicles (EVs)-based co-delivery system, termed EVs@N+A, loaded with acacetin and β-Nicotinamide mononucleotide (NMN). This nanoplatform was designed to leverage its inherent affinity for the testicular microenvironment. The study investigated the in vivo effects of EVs@N+A on sperm function in a model of asthenozoospermia, assessing parameters like sperm count, motility, and progressive movement.

The EVs@N+A nanoplatform demonstrated targeted accumulation within the testicular microenvironment. Upon release, acacetin initiated a potent anti-ferroptotic response, specifically by upregulating the expression of GPX4 and SLC7A11 and significantly suppressing lipid peroxidation. Concurrently, NMN effectively elevated intracellular NAD+ levels, which in turn reprogrammed cellular metabolism and restored ATP production. > This dual strategy, combining ferroptosis inhibition with metabolic rejuvenation, effectively rescued sperm function, leading to enhanced sperm count, motility, and progressive movement in vivo. The intrinsic AIE properties of acacetin also enabled simultaneous high-contrast imaging and tracking of the therapeutic agent, establishing a self-monitored theranostic platform.