A tumor-targeting porphyrin-micelle with enhanced STING agonist delivery and synergistic photo-/immuno- therapy for cancer treatment

Yuqing Pan; Haijing Qu; Han Chen; Wei Cheng; Zhiran Duan; Jiaojiao Yang; Ning Wang; Jie Wu; Yanjun Wang; Chao Wang; Xiangdong Xue

doi:10.1016/j.actbio.2024.12.059

A tumor-targeting porphyrin-micelle with enhanced STING agonist delivery and synergistic photo-/immuno- therapy for cancer treatment

Acta Biomater. 2024 Dec 31:S1742-7061(24)00779-7. doi: 10.1016/j.actbio.2024.12.059. Online ahead of print.

Authors

Yuqing Pan¹, Haijing Qu¹, Han Chen¹, Wei Cheng¹, Zhiran Duan¹, Jiaojiao Yang², Ning Wang¹, Jie Wu¹, Yanjun Wang², Chao Wang², Xiangdong Xue³

Affiliations

¹ Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China; National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai 200240, China.
² Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
³ Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China; National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: xuexd@sjtu.edu.cn.

PMID: 39746530
DOI: 10.1016/j.actbio.2024.12.059

Abstract

The activation of STING pathway has emerged as a promising strategy in cancer immunotherapy. However, challenges associated with unfavorable physicochemical properties and potential off-target toxicities have limited the application of STING agonists. Here, we develop an amphiphilic and cationic charged porphyrin-polymer to electrostatically load the STING agonist (MSA-2) within a micellar structure, thereby enhancing carrier compatibility and drug-loading content of MSA-2. Additionally, tumor-targeting ligands were functionalized onto the micelle to enhance specificity for tumor cells, aiming to significantly improve tumor accumulation while minimizing undesirable toxicity. The resultant tumor-targeting porphyrin micelle (TPC@M) seamlessly integrates three therapeutic mechanisms: i) tumor ablation via phototherapy; ii) robust activation of the STING pathway by MSA-2; iii) synergistic photo-/immuno- stimulations. TPC@M efficiently ablates primary tumors through phototherapy and further activates adaptive immune responses synergistically with MSA-2-induced innate immunity to suppress metastasis and prevent recurrence. Overall, we transformed a delivery-compromised therapeutic into a precise, stable, and safe nanomedicine that unleashes synergistic immunotherapeutic effects. STATEMENT OF SIGNIFICANCE: This study addresses the urgent need for an efficient delivery system to fully harness the potential of the STING agonist MSA-2 in cancer immunotherapy. The cGAS-STING pathway plays a critical role in modulating anti-tumor immunity; however, the clinical application of MSA-2 has been hindered by its poor physicochemical properties and off-target effects. Our innovative approach introduces a tumor-targeting porphyrin-based polymeric micelle (TPC@M) that efficiently encapsulates MSA-2, overcoming compatibility issues associated with traditional nanocarriers. The TPC@M not only exhibits enhanced tumor targeting and reduced toxicity but also integrates phototherapy with immunotherapy, providing a synergistic strategy for cancer treatment. Our in vivo findings using 4T1 breast cancer mouse models demonstrate significant inhibition of tumor growth and prevention of metastasis, accompanied by a robust and long-lasting immune response.

Keywords: STING activation; drug delivery; nanomedicine; phototherapy.