Neuroinflammation is a key feature of Alzheimer’s disease (AD) and plays a significant role in its progression. In AD brains, the downregulation of a special enzyme, SphK1, impairs lipid homeostasis, which, in turn, downregulates the generation of specialised pro-resolving mediators (SPMs) that disrupt the inflammation-resolving mechanism and clearance of Aβ. This shifts neuronal cells towards a chronic pro-inflammatory phenotype, exacerbating neurotoxicity. In this work, we present a porous MnO2 based nanoplatform to mitigate neuroinflammation in AD. These nanoparticles were loaded with defensamide to activate SphK1, coated with a thin layer of PDA to act as a gatekeeper and then conjugated with the ApoE3 protein to effectively enhance cellular targeting. Acellular ROS generation experiments confirmed the excellent ROS scavenging activity of defensamide, PDA and MnO2 nanoparticles. The ROS-scavenging ability of DMP reduces oxidative stress in the brain, and defensamide is involved in reducing inflammatory molecules, thereby exerting a synergistic anti-inflammatory effect. Furthermore, in vitro studies on SH-SY5Y neuroblastoma cells showed that DMPA exhibited low ROS levels and improved cell viability following amyloid-beta treatment, indicating potential neuroprotective effects. The current nanoplatform offers a promising targeted approach to modulate neuroinflammation and support AD therapy development.