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<p>Sleep is increasingly recognized as a critical determinant of brain clearance and drug biodistribution via the glymphatic system. The present study introduces a chronotherapeutic nanogel platform for sleep-synchronized intranasal delivery of 7,8-dihydroxyflavone (7,8-DHF), a small-molecule TrkB agonist with poor aqueous solubility and blood–brain-barrier permeability. Thermoresponsive chitosan–Poloxamer 407 nanogels were prepared by the cold method and optimized (NG-8) using factorial design. The optimized nanogel exhibited a sol–gel transition near 32&#xa0;°C, nanoscale particle size (158 ± 12&#xa0;nm), PDI 0.24 ± 0.05, zeta potential + 21 mV, and high entrapment efficiency (89 ± 4%). Rheological and stability analyses confirmed reversible gelation and colloidal integrity over 30 days. In-vitro release followed Higuchi–Peppas kinetics (r² = 0.985, <i>n</i> = 0.46), indicating Fickian diffusion. Ex-vivo permeation across zebrafish olfactory mucosa revealed a 2.3-fold enhancement in permeability coefficient versus free drug. In-vivo pharmacokinetics demonstrated a 2.8-fold increase in brain AUC and a threefold higher brain-to-plasma ratio during sleep-phase dosing, validating glymphatic-mediated transport. Behavioral assays showed complete restoration of spatial (SAB 79 ± 3%) and recognition memory (DI 0.36 ± 0.04) in scopolamine-challenged zebrafish, supported by normalization of antioxidant biomarkers (↑ SOD, ↑ GSH, ↓ MDA) and intact neuronal histology. Collectively, these results establish that thermoresponsive 7,8-DHF nanogels, administered during sleep, can harness glymphatic flow for targeted, sustained neurodelivery. The concept of sleep-synchronized glymphatic-activated nanomedicine introduces a transformative paradigm for CNS drug targeting. </p>

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Sleep-Synchronized Glymphatic-Activated Intranasal Nanogels for Enhanced Neurodelivery of 7,8-Dihydroxyflavone: a Chronotherapeutic Investigation

  • 期刊论文

  • 发表日期：

    2026年2月20日

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  • Dilpreet Singh

摘要

Sleep is increasingly recognized as a critical determinant of brain clearance and drug biodistribution via the glymphatic system. The present study introduces a chronotherapeutic nanogel platform for sleep-synchronized intranasal delivery of 7,8-dihydroxyflavone (7,8-DHF), a small-molecule TrkB agonist with poor aqueous solubility and blood–brain-barrier permeability. Thermoresponsive chitosan–Poloxamer 407 nanogels were prepared by the cold method and optimized (NG-8) using factorial design. The optimized nanogel exhibited a sol–gel transition near 32 °C, nanoscale particle size (158 ± 12 nm), PDI 0.24 ± 0.05, zeta potential + 21 mV, and high entrapment efficiency (89 ± 4%). Rheological and stability analyses confirmed reversible gelation and colloidal integrity over 30 days. In-vitro release followed Higuchi–Peppas kinetics (r² = 0.985, n = 0.46), indicating Fickian diffusion. Ex-vivo permeation across zebrafish olfactory mucosa revealed a 2.3-fold enhancement in permeability coefficient versus free drug. In-vivo pharmacokinetics demonstrated a 2.8-fold increase in brain AUC and a threefold higher brain-to-plasma ratio during sleep-phase dosing, validating glymphatic-mediated transport. Behavioral assays showed complete restoration of spatial (SAB 79 ± 3%) and recognition memory (DI 0.36 ± 0.04) in scopolamine-challenged zebrafish, supported by normalization of antioxidant biomarkers (↑ SOD, ↑ GSH, ↓ MDA) and intact neuronal histology. Collectively, these results establish that thermoresponsive 7,8-DHF nanogels, administered during sleep, can harness glymphatic flow for targeted, sustained neurodelivery. The concept of sleep-synchronized glymphatic-activated nanomedicine introduces a transformative paradigm for CNS drug targeting.