Split-Deliver-Click: Tumor-Specific Protein Degradation via "AND" Logic-Gated In-Cell Bioorthogonal Clicking of...

Area of Science:

• Biochemistry
• Molecular Biology
• Nanotechnology

Background:

• PROteolysis TArgeting Chimeras (PROTACs) offer targeted protein degradation but face challenges like low bioavailability and off-target effects.
• Developing strategies for efficient and specific PROTAC delivery is crucial for clinical translation.

Purpose of the Study:

• To develop a novel nanoplatform for tumor-specific PROTAC generation and protein degradation.
• To overcome limitations of traditional PROTACs by enabling in-situ PROTAC formation via bioorthogonal click chemistry.

Main Methods:

• PROTACs were split into click-reactive precursors.
• A "AND" logic-gated nanodelivery system was designed, activated by tumor-specific enzymes (legumain and cathepsin B).
• In-cell click chemistry was employed to reassemble PROTACs (Click-PROTACs) at the tumor site.

Main Results:

• The Split-Deliver-Click strategy enabled efficient and specific protein degradation.
• The logic-gated system ensured tumor-specific release of PROTAC precursors.
• In-situ PROTAC generation via click chemistry was successfully demonstrated.

Conclusions:

• The Split-Deliver-Click nanoplatform represents a promising approach for precise, tumor-targeted protein degradation.
• This strategy enhances PROTAC efficacy and specificity, potentially improving therapeutic outcomes.