AND-Gate-Enabled Extra-Small Nanoparticles Achieve Deep Penetration and Long Retention in Large Tumors for Efficient Cancer Stem Cells Dismission

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 <i>in situ</i> 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.