Introduction: Microglial hyperactivation-driven neuroinflammation is a major driver of secondary brain injury following cerebral ischemia/reperfusion (I/R), yet effective therapies targeting this pathological process remain limited. Marine-derived sulfated polysaccharides have emerged as promising anti-inflammatory agents, but the therapeutic potential and mechanisms of Laminaria japonica polysaccharide (LJP) in cerebral I/R injury are poorly understood. Methods: LJP was isolated from Laminaria japonica and structurally characterized via high-performance gel permeation chromatography (HPGPC), Fourier-transform infrared (FT-IR) spectroscopy, and ion chromatography. Its neuroprotective effects were evaluated in a mouse model of transient middle cerebral artery occlusion (tMCAO), with assessments of infarct volume, neurological function, and neuroinflammatory markers. Cross-species transcriptomic analysis identified potential targets, which were validated through in vivo and in vitro functional assays (rescue experiments with recombinant Csf3 and neutralization assays with Csf3-specific antibodies). Results: Structural characterization confirmed LJP is enriched in fucose, galacturonic acid, glucuronic acid, and sulfate groups. In tMCAO mice, LJP administration reduced infarct volume, improved neurological function, and suppressed microglial pro-inflammatory polarization, accompanied by decreased levels of interleukin-1b (IL-1b), tumor necrosis factor-α (TNFα), and interleukin-6 (IL-6). Transcriptomic analysis identified granulocyte colony-stimulating factor (Csf3/G-CSF) as a potential LJP-regulated mediator. Recombinant Csf3 partially reversed LJP’s protective effects, while Csf3-specific antibodies failed to enhance LJP’s anti-inflammatory benefits, suggesting Csf3 as an important contributory mechanism. Discussion: These findings demonstrate that LJP mitigates acute neuroinflammation post-I/R at least partly through Csf3 suppression, highlighting its promise as a novel phytotherapeutic agent for ischemic stroke.

Alzheimer’s disease (AD) is a common neurodegenerative disorder with limited effective treatments. Cod skin collagen peptides (CSCPs) have neuroprotective potential for AD but face poor bioavailability—due to gastrointestinal enzyme cleavage and hepatic first-pass metabolism—prompting this study to develop a nanodelivery system to enhance CSCPs’ efficacy. Trimethyl chitosan (TMC)-based CSCP-loaded nanoparticles (CSCPs-NPs) were synthesized via ionic gelation, characterized for physicochemical properties, and tested in a D-galactose-induced AD mouse model (six groups: normal control, model, CSCPs low/high dose, blank NPs, CSCPs-NPs) using behavioral tests, histopathology, immunohistochemistry, and ELISA. CSCPs-NPs had a hydrodynamic diameter of 93.25 ± 21.52 nm, polydispersity index of 0.18 ± 0.13, 61.17% encapsulation efficiency, and sustained 24 h release. In AD mice, CSCPs-NPs significantly improved cognitive function and motor coordination, reduced hippocampal atrophy, preserved neurons, and mitigated oxidative stress, neuroinflammation, and apoptosis (upregulated Bcl-2, downregulated Bax)—effects matching high-dose free CSCPs. This TMC-based nanoformulation enhances CSCPs’ bioavailability and provides a promising strategy for AD intervention.