Genotype-specific precision tumor therapy using mitochondrial DNA mutation-induced drug release system

Area of Science:

• Biomedical Engineering
• Molecular Biology
• Oncology

Background:

• Targeting tumor cells while sparing healthy tissue remains a significant challenge in cancer therapy.
• Mitochondrial DNA (mtDNA) mutations are prevalent in cancer and influence metabolic homeostasis, presenting a potential therapeutic target.
• Developing precise drug delivery systems that respond to specific genetic markers is crucial for personalized medicine.

Purpose of the Study:

• To design and evaluate a mutation-induced drug release system (MIDRS) for precise tumor cell killing.
• To utilize Cas12a's capabilities for recognizing single-nucleotide variations (SNVs) in mtDNA for targeted drug delivery.
• To investigate the potential of MIDRS in triggering both innate and adaptive immune responses for enhanced cancer treatment.

Main Methods:

• Development of a mutation-induced drug release system (MIDRS) based on Cas12a's SNV recognition and trans-cleavage activity.
• Utilizing Ce6 as a model drug for organelle-level photodynamic therapy.
• In vivo evaluation in unilateral, bilateral, and heterogeneous tumor models to assess antitumor efficacy and specificity.

Main Results:

• MIDRS successfully identified tumor tissues with specific mtDNA SNVs, enabling precise intracellular drug release.
• Organelle-level photodynamic therapy via MIDRS demonstrated significant antitumor effects (~82.6%) without harming normal cells.
• The system effectively triggered both innate and adaptive systemic antitumor immune responses.
• MIDRS showed versatility for genotype-specific release of chemotherapeutic drugs.

Conclusions:

• MIDRS offers a precise and effective strategy for tumor cell killing by targeting specific mtDNA mutations.
• The system holds promise for personalized cancer treatment by enabling genotype-specific drug delivery and enhancing antitumor immunity.
• This approach represents a significant advancement in developing mutation-specific, personalized therapeutic strategies for cancer.