A Nucleic Acid-Based LYTAC Plus Platform to Simultaneously Mediate Disease-Driven Protein Downregulation

Area of Science:

• Biomaterials Science
• Molecular Biology
• Therapeutic Drug Development

Background:

• Protein degradation techniques like PROTACs and LYTACs offer therapeutic potential but require enhanced efficacy for complex diseases.
• Current methods face limitations in addressing intricate disease mechanisms, necessitating innovative approaches.

Purpose of the Study:

• To engineer a novel LYTAC Plus hydrogel by integrating gene silencing with LYTAC technology for improved therapeutic outcomes.
• To demonstrate the dual functionality of the LYTAC Plus hydrogel in simultaneously degrading target proteins and silencing specific genes.

Main Methods:

• Development of a nucleic acid self-assembled hydrogel incorporating VEGFR-binding peptides and M6P moieties for LYTAC capability.
• Utilizing siRNAs targeting ANG-2 as cross-linkers to impart gene silencing ability, creating the LYTAC Plus hydrogel.
• In vitro and in vivo assessments to evaluate the hydrogel's efficacy in reducing VEGFR-2 and ANG-2 levels.

Main Results:

• The LYTAC Plus hydrogel successfully integrated both LYTAC and gene silencing functionalities.
• Simultaneous reduction of VEGFR-2 and ANG-2 levels was observed both in vitro and in vivo.
• Significant therapeutic improvements were noted in a mouse model of neovascular age-related macular degeneration.

Conclusions:

• The LYTAC Plus hydrogel represents a versatile platform with dual therapeutic actions, enhancing protein degradation and gene silencing.
• This innovative hydrogel shows considerable potential for treating various diseases, including neovascular age-related macular degeneration.
• Further research is warranted to explore the broad applicability and therapeutic advantages of the LYTAC Plus hydrogel.