Camouflaged Nanorobots Target and Drive the Subcellular Organelle Crosstalk Pattern of Innate Immune Cells to Promote Neural Regeneration

Macrophage (Mφ) phenotypic transformation is crucial in determining spinal cord injury (SCI) outcomes. However, the suborganelle crosstalk mechanisms—particularly between the endoplasmic reticulum (ER) and mitochondria—that mediate Mφ subgroup conversion during SCI remain underexplored. We integrated niche intervention strategies and omics sequencing to investigate the effects of ER stress (ERS)–mitochondrial metabolic crosstalk. Subsequently, we developed a dual-targeted camouflaged nanorobot (BP@D/N) that can reach the SCI site via systemic circulation and selectively interact with Mφ. We observed that Ero1α-mediated Ca ²⁺ shuttling is an important mechanism for locking the inflammatory phenotype of Mφ. By blocking the Ero1α/MAM/mtCa ²⁺ axis, suppressed mtDNA release, and downregulated the cGAS–STING–NFκB signaling cascade, thus promoting M2 polarization and neural repair. Our study clarified the regulatory mechanism of Mφ transformation-associated suborganelle crosstalk and contributed a brand-new paradigm for reconstructing the dynamic balance of immune–neural interactions in the SCI microenvironment for effective repair. It offers a scientifically grounded and translational approach to overcoming the clinical challenge of irreversible SCI.