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Ultrasound-responsive spherical nucleic acid against c-Myc/PD-L1 to enhance anti-tumoral macrophages in triple-negative breast cancer progression

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Abstract

Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype because of its aggressive behavior and limited therapeutic targets. c-Myc is hyperactivated in the majority of TNBC tissues, however, it has been considered an “undruggable” target due to its disordered structure. Herein, we developed an ultrasound-responsive spherical nucleic acid (SNA) against c-Myc and PD-L1 in TNBC. It is a self-assembled and carrier-free system composed of a hydrophilic small-interfering RNA (siRNA) shell and a hydrophobic core made of a peptide nucleic acid (PNA)-based antisense oligonucleotide (ASO) and a sonosensitizer. We accomplished significant enrichment in the tumor by enhanced permeability and retention (EPR) effect, the controllable release of effective elements by ultrasound activation, and the combination of targeted therapy, immunotherapy and physiotherapy. Our study demonstrated significant anti-tumoral effects in vitro and in vivo. Mass cytometry showed an invigorated tumor microenvironment (TME) characterized by a significant alteration in the composition of tumor-associated macrophages (TAM) and decreased proportion of PD-1-positive (PD-1+) T effector cells after appropriate treatment of the ultrasound-responsive SNA (USNA). Further experiments verified that tumor-conditioned macrophages residing in the TME were transformed into the anti-tumoral population. Our finding offers a novel therapeutic strategy against the “undruggable” c-Myc, develops a new targeted therapy for c-Myc/PD-L1 and provides a treatment option for the TNBC.

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Acknowledgement

This work was supported by the National Natural Science Foundation of China (81920108029, 22077063, 22322703) and the Key Foundation for Social Development Project of Jiangsu Province of China (BE2021741).

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  1. Contributed equally to this work

Authors and Affiliations

  1. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

    Runtian Wang, Fangyan Gao, Feng Xu, Xintong Li & Xiaoxiang Guan

  2. State Key Laboratory of Analytical Chemistry for Life Sciences, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, 210023, China

    Gaigai Li & Jinbo Li

  3. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    Jian Zhang

  4. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Jian Zhang

  5. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China

    Xiaoxiang Guan

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  1. Runtian Wang
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  2. Gaigai Li
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  3. Fangyan Gao
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  4. Feng Xu
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  7. Jinbo Li
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Correspondence to Jian Zhang, Jinbo Li or Xiaoxiang Guan.

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Wang, R., Li, G., Gao, F. et al. Ultrasound-responsive spherical nucleic acid against c-Myc/PD-L1 to enhance anti-tumoral macrophages in triple-negative breast cancer progression. Sci. China Life Sci. 67, 698–710 (2024). https://doi.org/10.1007/s11427-023-2433-y

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