COF@DNAzyme Empowering Endogenous Copper for One-Stitch Bioorthogonal Catalysis-Based Anticancer Therapy

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Drug Delivery

Background:

• Bioorthogonal chemistry, especially copper-catalyzed azide-alkyne cycloaddition (CuAAC), offers potential for in situ prodrug activation.
• Current methods using exogenous copper catalysts risk disrupting homeostasis and face deactivation.
• Staggered administration of catalysts and prodrugs complicates clinical use and timing.

Purpose of the Study:

• To develop a "one-stitch" bioorthogonal catalytic therapy system utilizing endogenous copper.
• To overcome limitations of exogenous catalysts and staggered administration in prodrug activation.
• To create a safe, synchronized, and clinically translatable nanoplatform for localized drug synthesis.

Main Methods:

• Constructed covalent organic framework (COF) nanoparticles co-delivering DNAzyme CLICK-17 and tumor-targeting aptamer AS1411 (COF-P@C-A).
• Utilized tumor cell internalization, acidic environment, and glutathione (GSH) to trigger nanoparticle degradation and release of components.
• Leveraged released CLICK-17 to catalyze endogenous copper-mediated CuAAC reaction for prodrug activation.

Main Results:

• The nanoplatform successfully co-delivered catalyst and prodrugs, releasing them upon cellular uptake.
• Degradation of COF nanoparticles consumed GSH, alleviating copper sequestration and increasing endogenous Cu(I) availability.
• Localized CuAAC reaction by CLICK-17 efficiently synthesized drugs within tumor cells, maximizing therapeutic effect.

Conclusions:

• The developed COF-based nanoplatform enables synchronized, endogenous copper-catalyzed bioorthogonal prodrug activation.
• This strategy enhances therapeutic efficacy and minimizes systemic toxicity by localizing drug synthesis.
• The approach presents a safe, efficient, and clinically translatable advancement in bioorthogonal catalytic therapy.