Camouflaged nanorobots target and regulate macrophage subcellular organelle crosstalk patterns 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 aim to integrate niche intervention strategies and omics sequencing to investigate the effects of the metabolic crosstalk between ER stress (ERS) and mitochondria. Subsequently, we develop a dual-targeted camouflaged nanorobot (BP@D/N) that can reach the SCI site via systemic circulation and selectively interact with Mφ. We observe that Ero1α-mediated Ca2+ shuttling is an important mechanism for locking the inflammatory phenotype of Mφ. Blocking the Ero1α/MAMs/mtCa2+ axis suppresses mtDNA release and downregulates the cGAS-STING-NFκB signaling cascade, thus promoting M2 polarization and neural repair. Our study clarifies the regulatory mechanism of Mφ transformation-associated suborganelle crosstalk and offers a 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. Macrophages play an important role in repair and regeneration of damaged nerves in spinal cord injury (SCI). Here, Guo et al. investigate effects of endoplasmic reticulum-mitochondria crosstalk on macrophage phenotype and develop a targeted nanorobot inhibiting the Ero1α/MAMs/mtCa²⁺ axis, promoting M2 polarization and neural repair as a therapeutic strategy to treat SCI.