AND-Gate-Enabled Extra-Small Nanoparticles Achieve Deep Penetration and Long Retention in Large Tumors for Efficient...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Research

Background:

• Cancer stem cells (CSCs) drive therapeutic failure and tumor relapse.
• Nanoparticle drug delivery faces a penetration-retention paradox in deep tumors.

Purpose of the Study:

• To develop extra-small iron oxide nanoparticles (IO) that achieve deep tumor penetration and long retention.
• To engineer an "AND logic-gate" self-assembly mechanism for enhanced nanoparticle performance.
• To enable efficient elimination of cancer stem cells (CSCs) in deep tumors.

Main Methods:

• Functionalized extra-small iron oxide nanoparticles (TIO-TK-PEG@LAP) with a pH-sensitive linker and β-lapachone (LAP).
• Utilized an "AND logic-gate" system involving H2O2, H+, and tyrosine (T) residues for in situ self-assembly into IO aggregates.
• Investigated the synergistic effect of released iron ions (Fe2+) and LAP-generated H2O2 to induce ferroptosis via Fenton reaction.

Main Results:

• Achieved deep tumor penetration with extra-small TIO-TK-PEG@LAP nanoparticles.
• Demonstrated in situ self-assembly into larger aggregates (∼100 nm) for prolonged tumor retention.
• Showcased efficient CSC dismission through ferroptosis induction via amplified Fenton reaction.

Conclusions:

• The developed nanoparticles effectively address the penetration-retention paradox in deep tumors.
• The "AND logic-gate" self-assembly strategy enhances nanoparticle efficacy for cancer therapy.
• This approach offers a promising strategy for overcoming therapeutic resistance driven by cancer stem cells.