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Theranostics 2022; 12(12):5299-5316. doi:10.7150/thno.74550 This issue Cite

Research Paper

Accurate programmed multifunctional nano-missiles for self-promoted deep delivery and synergistic cascade tumor therapy: Tactfully collaborating chemosynthesis with tumor microenvironment remodeling

Runxin Lu^1✉, Siqi Wang², Zhongzhen Yang², Lin Zhou², Chunyan Yang², Yong Wu^2✉

1. Department of Pharmacy, Evidence-Based Pharmacy Center, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), West China Second University Hospital, Sichuan University, Chengdu, China.
2. Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China.

✉ Corresponding authors: E-mail: lurunxinedu.cn (Runxin Lu), wyongedu.cn (Yong Wu).

Abstract

Rationale: Triple-negative breast cancer (TNBC) is considered one of the highest-risk subtypes of breast cancer and has dismal prognosis. The management of aggressive TNBC remains a formidable challenge. Tumor microenvironment (TME), with the unique features, which can serve as the “soil” for the growth and survival of tumor cells (the “seeds”), plays an important regulatory role in the occurrence, proliferation and metastasis of tumors. Catalytic tumor therapy, which can destroy the homeostasis of TME, affect the occurrence and progress of tumors in an all-round way and further magnify chemotherapy, is a quite potential tactic for TNBC-treatment.

Methods: Herein, accurate programmed multifunctional cascade nano-missiles (GOx+L-Arg-NM/PTX-NM) composed of novel intelligent all-in-one “nano-rocket” (the drug delivery system) and “ammunitions” (the therapeutic agents) are innovatively constructed by mimicking the functionalities of military precision-guided missiles. Ammunitions can be precisely and effectively transported to the core region of TNBC (the “battlefield”) by organic modification on the surface of nano-rocket via chemical means. Once successfully internalized by TNBC cells, the nano-missiles can automatically trigger relevant cascade reactions without external stimulation, prominently disrupt the homeostasis of TME, and produce a “bomb-like” attack on tumors, further promoting the chemotherapy.

Results: Both in vitro and in vivo investigations indicated that the innovative nano-missiles could deliver ammunitions to the core area of TNBC to the utmost extent, dramatically ablate tumor and restrain tumor metastasis via orchestrated multimodal synergistic starvation/oxidation/gas/chemotherapy.

Conclusion: The well-designed multifunctional nano-missiles may emerge as a new paradigm to suppress the malignant proliferation and metastasis of TNBC, offering a promising approach for the next generation cancer therapy.

Keywords: programmed nanodrug, chemosynthesis, tumor microenvironment remodeling, self-promoted drug delivery, multimodal synergistic therapy

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