ANDゲートにより可能になった超小型ナノ粒子は、がん幹細胞を効率的に除去するために大型腫瘍への深い浸透と長期保持を達成

The persistence of cancer stem cells (CSCs) within deep tumors is a primary driver of therapeutic failure and relapse. Most large nanoparticles fail to penetrate deep tumors, and extra-small nanoparticles suffer from poor retention in tumors. To solve the "penetration-retention paradox", herein, we developed special extra-small iron oxide nanoparticles (IO) featuring an "AND logic-gate"-driven self-assembly to achieve both deep penetration and long retention in large tumors for efficient CSCs dismission. Typically, the poly(ethylene glycol) (PEG) shield of IO is functionalized with a tyrosine (T) and thioketal (TK) linker followed by β-lapachone (LAP) loading, forming TIO-TK-PEG@LAP. (i) The extra-small TIO-TK-PEG@LAP can penetrate into deep tumors, whose H₂O₂ cleaves the TK linker, detaching the PEG shield and exposing T residues. (ii) The H⁺ facilitates the release of Fe²⁺ from IO to react with H₂O₂, generating hydroxyl radicals (^•OH). (iii) The ^•OH catalyzes covalent cross-linking of T residues, driving in situ self-assembly into IO aggregates (∼100 nm), prolonging tumor retention. (iv) After cellular uptake, the IO aggregates are degraded in the endosomes, releasing LAP and Fe²⁺. (v) LAP can be catalyzed to generate substantial H₂O₂, which synergizes with Fe²⁺ to amplify the Fenton reaction, generating explosive ^•OH to trigger ferroptosis of tumor cells.