Targeted Delivery of CNS‐Specific Hesperidin as a Leptin Sensitizer for Treating Obesity‐Associated Sleep‐Disordered Breathing

Abstract Obesity‐associated obstructive sleep apnea (OSA) highlights the need for effective therapies. Hypothalamic endoplasmic reticulum (ER) stress contributes to leptin resistance in obesity. Although hesperidin (HE) modulates ER stress and oxidative pathways, its low bioavailability limits clinical use, its role in OSA is unknown. Self‐assembled HE nanoparticles (HE NPs) are developed to address this. HE NPs are synthesized via solvent emulsification‐evaporation and tested in diet‐induced obese (DIO), lean, and ob/ob mice. In DIO mice, HE NPs reduce food intake, body weight, and plasma leptin while mitigating hypothalamic ER stress and boosting STAT3 phosphorylation, without toxicity, and they outperform HE and PLGA NPs. In ob/ob mice, HE NPs lower PERK phosphorylation and, with leptin, further suppress weight gain and food intake while enhancing STAT3 signaling. Combining HE NPs with leptin in DIO mice amplifies weight loss versus HE NPs alone. HE NPs also improve sleep‐disordered breathing, lowering the apnea index during non‐rapid eye movement sleep (17.1±3.5 to 9.3±3.0 events h ⁻¹ , P < 0.01) and rapid eye movement sleep (22.4±5.6 to 12.8±3.9 events h ⁻¹ , P < 0.05). The results demonstrate that HE NPs improve metabolic dysfunction and OSA in obesity by reducing ER stress and restoring leptin sensitivity, offering a novel therapeutic strategy.