Objective Post-ischemic acute inflammation and persistent dysregulated immune microenvironment exacerbate neuronal injury and severely limit functional recovery in ischemic stroke. To address this critical challenge, this study aims to engineer and systematically evaluate a biomimetic nanosystem composed of TGF-β1-loaded platelet membrane-camouflaged lipid nanoparticles (PLP), designed for dual lesion-targeted delivery and immune microenvironment remodeling. By verifying its precise accumulation, inflammatory modulation, and neuroprotective effects, we seek to resolve the key scientific challenge of achieving a synergistic, integrated intervention for lesion targeting, immune regulation, and functional recovery. Methods Physicochemical properties of PLP, including particle size, zeta potential, and morphology, were characterized via dynamic light scattering, zeta analysis, and electron microscopy, while membrane protein retention was verified by Western blotting. In vitro functional activities were seperately evaluated in LPS-induced M1-polarized RAW264.7 macrophages and an oxygen-glucose deprivation/reoxygenation (OGD/R) model in BV2 and SH-SY5Y cells. In vivo, a mouse transient middle cerebral artery occlusion (tMCAO) model was utilized to simulate ischemia-reperfusion injury. Spatiotemporal brain distribution of PLP was monitored via live fluorescence imaging, and therapeutic outcomes were comprehensively assessed using TTC staining, GFAP immunofluorescence, body weight monitoring, and neurological severity scores (NSS). Result PLP nanoparticles exhibited uniform morphology, negative surface charge, and effective retention of key platelet membrane adhesion and immunomodulatory proteins, demonstrating excellent biomimetic properties. We evaluate the optimal concentration in OGD/R-induced BV2 cells. In vitro, PLP significantly suppressed the polarization of RAW264.7 cells toward the pro-inflammatory M1 phenotype and reduced neuronal apoptosis under OGD/R conditions. In tMCAO mice, PLP rapidly accumulated in the ischemic hemisphere and sustained high-level retention for up to 7 days. Compared with controls, PLP treatment significantly reduced infarct volume, suppressed reactive astrogliosis, and accelerated the recovery of neurological function. Conclusion This study establishes a biomimetic nanoplatform that organically integrates active targeting mediated by platelet membrane-endothelial interactions with the anti-inflammatory, antioxidative, and neuroprotective functions of TGF-β1. PLP achieves rapid lesion homing and prolonged retention while synergistically modulating the post-stroke inflammatory microenvironment by inhibiting pro-inflammatory cell activation, reducing neuronal apoptosis, and limiting excessive astrocyte activation. These findings demonstrate that this combined "targeted delivery plus immune regulation" strategy effectively reverses the inflammatory microenvironment and improves neurological outcomes, providing a robust experimental basis for next-generation ischemic stroke therapeutics.