Microenvironment-informed carrier-free maltol-arginine nanoparticles harness CAT2-associated arginine transport for...

Spermatogenic disorders are a major cause of male infertility, with oxidative stress-driven Leydig cell dysfunction serving as a key pathological contributor. However, effective antioxidant therapy remains limited by insufficient accumulation in injured testes and by the formulation complexity associated with conventional carrier-based delivery systems. Here, we investigated the pathological microenvironment of di(2-ethylhexyl) phthalate (DEHP)-injured testes and found increased inducible nitric oxide synthase (iNOS) expression together with upregulation of the cationic amino acid transporter 2 (CAT2) in the testicular interstitium, indicating altered arginine metabolism and transport. Based on this pathological feature, we constructed carrier-free maltol-arginine nanoparticles (MAS) through Mannich reaction-mediated covalent conjugation and non-covalent self-assembly. In this system, the arginine moiety functions as a CAT2-recognizable structural cue for lesion-oriented delivery, whereas maltol provides antioxidant activity for redox regulation. MAS preferentially accumulated in injured testes and showed enhanced uptake by Leydig cells in vitro. Mechanistically, MAS promoted Nrf2 nuclear translocation, improved redox homeostasis, and attenuated NF-κB/NLRP3/GSDMD-mediated pyroptotic signaling. In the murine injury model, MAS ameliorated testicular microenvironmental disruption, improved Leydig cell-associated endocrine function, and enhanced sperm quality. Overall, this study presents a functionally engineered, carrier-free biomaterial strategy that redirects pathology-related arginine transport remodeling into a metabolic delivery advantage, providing a viable strategy for targeted intervention in spermatogenic disorders and restoration of testicular homeostasis.