Dual-Peptide Engineered Macrophage Membrane Biomimetic Nano-System via Targeting Rg1 Delivery for Traumatic Brain Injury Therapy

Abstract Traumatic brain injury (TBI) induces a detrimental inflammatory microenvironment at the lesion site, which, together with neuronal death and loss, leads to neurological dysfunction. The blood–brain barrier (BBB) further impedes intracerebral drug delivery, posing a major challenge for post-TBI therapy. To overcome this, we developed a brain-targeted biomimetic nano-system (R/T-MaM-NPs) using an engineered dual-peptide-modified macrophage membrane (MaM). This system encapsulates neuroprotective ginsenoside Rg1 into poly (lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs). RAW264.7 macrophages were engineered to co-express targeting peptides (RVG and T7) on their membranes; the derived R/T-MaM was then coated onto NPs. The MaM coating conferred high biocompatibility and biosafety, enabling R/T-MaM-NPs to reduce immune clearance and prolong systemic circulation. By leveraging the intrinsic inflammatory chemotaxis of MaM and dual-peptide targeting, the integrated system promoted traversal across the BBB and subsequent accumulation around the cerebral lesion, thereby inducing the transdifferentiation of reactive astrocytes (RAs) into electrophysiologically functional neuron-like cells (NLCs). RNA sequencing confirmed significant upregulation of neurogenic genes in R/T-MaM-NP-treated RAs, an outcome closely linked to suppression of the Wnt/Notch signaling pathway. Furthermore, R/T-MaM-NPs remodeled the inflammatory microenvironment at the TBI site, alleviated cerebral edema, and enhanced the recovery of cognitive and motor functions in TBI mice.