AIE-pharmacology-enabled organelle therapeutics for microplastic-induced asthenozoospermia

Microplastic pollution, particularly from polytetrafluoroethylene (PTFE), is an emerging threat to male fertility, driving spermatogenic impairment and asthenozoospermia through mitochondrial failure and ferroptosis-two interconnected pathologies that current therapies fail to address together. Herein, we introduce an "AIE-Pharmacology" strategy that transforms the natural product Hydroxysafflor Yellow A (HSYA) into a unique theranostic agent. We discover that HSYA possesses intrinsic aggregation-induced emission (AIE) properties, establishing a seamless "Drug-Probe Unity" wherein anti-ferroptotic pharmacology and self-reporting fluorescence are fused within a single molecule. Leveraging this attribute, we engineer living, functional mitochondria with HSYA to construct a bio-hybrid platform-Mito@H. This platform embodies a conceptual leap: mitochondria are no longer passive delivery vehicles but active therapeutic units that execute metabolic reprogramming by restoring NAD⁺/NADH redox balance and ATP synthesis, while the anchored HSYA concurrently suppresses ferroptosis via activation of the Nrf2/HO-1/SLC7A11/GPX4 axis. In a clinically relevant murine model of PTFE microplastic-induced asthenozoospermia, Mito@H administration strikingly rescues sperm count, progressive motility, and kinematic parameters, reconstitutes the complete spermatogenic lineage from spermatogonia to elongated spermatids, and reestablishes testicular redox homeostasis. This work pioneers a paradigm of organelle therapeutics powered by AIE-Pharmacology, offering a potent, precise, and translatable strategy to combat environmental toxicant-related male infertility and beyond.