AIE-pharmacology: Acacetin and NMN co-delivery rescues sperm motility

The emergence of aggregation-induced emission (AIE) luminogens has revolutionized biomedical theranostics, yet the exploration of natural AIE-active therapeutics remains nascent. Herein, we propose a novel "AIE-Pharmacology" paradigm, employing the natural flavonoid acacetin as an intrinsic AIEgen with pharmacological activity for self-monitored therapy of asthenozoospermia. Overcoming traditional aggregation-caused quenching (ACQ), acacetin utilizes its aggregation-enhanced emission and excited-state intramolecular proton transfer (ESIPT) properties to enable simultaneous treatment, high-contrast imaging, and tracking. We developed an extracellular vesicles (EVs)-based co-delivery system loaded with acacetin and β-Nicotinamide mononucleotide (NMN). This nanoplatform (EVs@N + A) exhibits inherent affinity for the testicular microenvironment. Upon targeted accumulation, released acacetin triggers a potent anti-ferroptotic response by upregulating GPX4 and SLC7A11 and suppressing lipid peroxidation. In parallel, NMN elevates intracellular NAD⁺ levels, reprogramming cellular metabolism and restoring ATP production. This dual strategy-inhibiting ferroptosis and rejuvenating metabolism-effectively rescues sperm function, enhancing sperm count, motility, and progressive movement in vivo. Our work reports acacetin as a multifunctional AIEgen in reproductive medicine and establishes a traceable theranostic platform, introducing the "AIE-Pharmacology" paradigm as a promising approach for treating male infertility and other diseases.