<p>Developing targeted treatment for glioblastoma is crucial but challenging. Herein, we propose a size-variable self-feedback nanomotor system, utilizing the unique high-calcium microenvironment of glioblastoma to prevent its progression through mitochondrial mineralization. It comprises three components: a self-feedback degradable lipid shell (containing nitric oxide-releasing lipid and nitric oxide-responsive degradable lipid), a motion nanomotor core (containing L-arginine derivatives and carboxyl-rich zwitterionic monomers for Ca²⁺ recruitment), and curcumin (inhibiting Ca²⁺ efflux). Nitric oxide-releasing lipid can be catalyzed by inducible nitric oxide synthase to release nitric oxide, triggering nitric oxide-responsive degradable lipid degradation. Initially, the larger nanomotors (~ 500 nm) penetrate the blood-brain barrier via chemotaxis towards glioblastoma microenvironment. During chemotaxis, the lipid shell gradually degrades, releasing smaller nanomotor core (~50 nm), which can target mitochondria and recruit Ca²⁺ to induce mitochondrial mineralization together with curcumin, inhibiting glioblastoma progression. This work may provide a glioblastoma-specific treatment strategy.</p>