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Targeted DNA Nanomachine Enables Specific miRNA-Responsive Singlet Oxygen Amplification for Precise Cutaneous
Hanane Aliouat1, Detian Zhang2,3, Lanyuan Peng2
1Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410013, China.
Abstract:
Photodynamic therapy (PDT) is a promising strategy for the treatment of skin-related tumors including cutaneous squamous cells carcinoma (cSCC). However, it is hard to balance the dosage off-target phototoxicity while maintaining satisfactory therapeutic effect. In addition, oxygen-dependent photosensitizers (PSs) are affected by tumor hypoxic environment, which further causes inefficient photocatalysis and reduces therapeutic effect. Herein, an intelligent DNA nanomachine based on tetrahedral DNA framework is proposed, incorporated with tumor-targeted aptamer and specific miRNA-responsive hairpin DNA catalytic assembly (HCA), for precise and high-efficient therapy of cSCC. After aptamer-mediated targeted delivery, a cSCC-specific miRNA selected by tissue sequencing analysis is used to activateHCA, for amplifying PSs and controllably releasing chemotherapeutic drugs. Sequential recognition can greatly improve tumor-specific accumulation and high-dose activation. Moreover, hemin is incorporated into DNA to catalytically produce oxygen. In vitro and in vivo experiments demonstrated that this DNA nanomachine greatly improved anti-tumor effect and realized effective ablation of cSCC in mice, with barely systemic toxicity and inflammation. It is anticipated that this strategy will promote biomedical applications of tumor-specific miRNA and provide a promising option for the non-invasive treatment of skin-associated tumors.
Insights
This study introduces a DNA nanomachine for precise photodynamic therapy (PDT) of skin cancer. The intelligent system targets tumors, releases drugs, and produces oxygen, significantly improving treatment efficacy with minimal toxicity.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Photodynamic therapy (PDT) shows promise for skin tumors like cutaneous squamous cell carcinoma (cSCC).
- Challenges include balancing therapeutic effect with off-target phototoxicity and overcoming tumor hypoxia affecting oxygen-dependent photosensitizers.
- Inefficient photocatalysis and reduced therapeutic outcomes are common issues in hypoxic tumor environments.
Purpose of the Study:
- To develop an intelligent DNA nanomachine for precise and high-efficiency therapy of cSCC.
- To address challenges of off-target toxicity and tumor hypoxia in PDT.
- To leverage tumor-specific miRNA for targeted drug delivery and enhanced therapeutic effect.
Main Methods:
- A tetrahedral DNA framework nanomachine was designed, incorporating a tumor-targeted aptamer and miRNA-responsive hairpin DNA catalytic assembly (HCA).
- Aptamer-mediated delivery facilitated targeted accumulation in cSCC.
- miRNA-activated HCA amplified photosensitizers and released chemotherapeutics; hemin was included to generate oxygen.
Main Results:
- The DNA nanomachine demonstrated enhanced tumor-specific accumulation and high-dose activation.
- In vitro and in vivo experiments showed significantly improved anti-tumor effects and effective cSCC ablation in mice.
- The treatment exhibited minimal systemic toxicity and inflammation.
Conclusions:
- The developed DNA nanomachine offers a precise and efficient strategy for cSCC therapy.
- This approach effectively overcomes PDT limitations like phototoxicity and hypoxia.
- The study highlights the potential of tumor-specific miRNA-based strategies for non-invasive skin cancer treatment.
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