Molecular Gardening for Neuroinflammation via Nose-to-Brain Delivery: A Ca²⁺ Responsive DNA Nanocage-Hydrogel System...

Intranasal administration offers a rapid and non-invasive route to deliver therapeutics directly from the nasal cavity into the brain for treating central nervous system (CNS) disorders. However, its efficacy is hampered by limited CNS targeting efficiency and rapid clearance in the nasal microenvironment. Here, a Ca²⁺ responsive alginate hydrogel drug delivery system (namely SA@T^SCC) encapsulating a STING inhibitor within a neuronal targeting aptamer-modified DNA nanocage for intranasal administration is developed. SA@T^SCC demonstrates enhanced nasal retention, sustained release, and efficient transport of cargo into the CNS, leading to robust accumulation in the brain and spinal cord of experimental autoimmune encephalomyelitis (EAE) mice, eventually promoting remyelination, suppressing neuroinflammation, and restoring motor function. Mechanistically, SA@T^SCC, acting as a molecular "gardener" in the diseased CNS "ecosystem," could directly repair "stressed plants" neurons by inhibiting STING-autophagy-ferroptosis, restore neuronal health instead of broadly spraying "pesticides" immunosuppressants, calm "disrupted pollinators" microglia, and reverse neuroinflammation. Despite the exploration of STING inhibition for EAE treatment, the concept of nose-to-brain drug delivery and neuron targeting intranasal platform enabling precise modulation of the CNS microenvironment could be further extended for other chronic neurodegenerative diseases.