Collagenase Degradable Biomimetic Nanocages Attenuate Porphyromonas gingivalis Mediated Neurocognitive Dysfunction via Targeted Intracerebral Antimicrobial Photothermal and Gas Therapy

Porphyromonas gingivalis (P.g.), a pathogen linked to periodontitis, is reported to be associated with severe neurocognitive dysfunction. However, there are few reports focusing on improving neurological function in the brain by eliminating P.g.. Therefore, we developed a core-shell nanocomposite for targeted intracerebral P.g. clearance and ameliorating neurocognitive impairments, Pt-Au@C-P.g.-MM, consisting of platinum nanoparticles (Pt NPs) encapsulated within Au nanocages (Pt-Au) as the core and a shell made of collagen and macrophage membranes from macrophage pretreated with P.g. (C-P.g.-MM). This design enhanced the nanocomposite's ability to cross the blood-brain barrier (BBB) and specifically target intracerebral P.g. through coating of P.g.-MM. Pt-Au@C-P.g.-MM depended on collagen to neutralize excessive collagenase from P.g., promoting its directed migration toward P.g.. Au nanocages exhibited excellent photothermal effects under near-infrared (NIR) laser irradiation, while Pt NPs also provided an efficient antibacterial gas therapy by generating oxygen to expose anaerobic P.g.. As a result, Pt-Au@C-P.g.-MM contributed to a synergistic antibacterial therapy and significantly reduced P.g. mediated neurocognitive dysfunction in periodontitis mice induced by oral P.g. infection. Based on the insights provided by the transcriptome sequencing analysis, anti-P.g. activity of Pt-Au@C-P.g.-MM facilitated the transition of microglia from the M1 to M2 phenotype by stimulating the PI3K-Akt pathway and reducing neuronal damage through the Wnt/β-catenin pathway.