Hybrid dextran/fibronectin nanogels for brain-targeted mitophagy inducer delivery to alleviate neuroinflammation and neuronal loss of Parkinson's disease.

Parkinson's disease (PD) is characterized by progressive dopaminergic neuron loss, chronic neuroinflammation, and α-synuclein aggregation. Blood-brain barrier (BBB)-penetrable, dual-target nanomedicines for microglial inflammation and neuronal degeneration remain challenging. In this study, we fabricated a brain-targeted, pH- and reactive oxygen species (ROS)-responsive nanogel (NG) platform using dextran (Dex) as the main polysaccharide backbone, crosslinked with inflammation-targeting fibronectin (FN), and loaded with neuroprotective quercetin (Que). Dex-FN/Que NGs exhibited a uniform spherical morphology with an average diameter of 187 nm, favorable colloidal stability, and stimuli-triggered drug release behavior. Abundant hydroxyl groups on Dex enabled efficient BBB penetration, while FN mediated integrin-dependent internalization in microglia and neurons. These NGs suppressed the nuclear factor-kappa B (NF-κB) signaling pathway, scavenged ROS, promoted favorable microglial polarization, and balanced oxidative stress. Meanwhile, mitophagy flux activated by the NGs in neurons exerted strong neuroprotection effect. In a mouse model of PD, Dex-FN/Que NGs effectively crossed the BBB and accumulated in injured brain regions, significantly protecting dopaminergic neurons, improving motor function, and relieving depressive-like behaviors. Therapeutic benefits arose from normalized microglial polarization, reduced oxidative stress, and inhibited neuronal ferroptosis. This Dex-based stimuli-responsive nanoplatform provides a promising brain-targeted strategy for the treatment of PD and other neurological disorders.