A nanotherapeutic strategy to overcome chemotherapeutic resistance of cancer stem-like cells


Tumour heterogeneity remains a major challenge in cancer therapy owing to the different susceptibility of cells to chemotherapy within a solid tumour. Cancer stem-like cells (CSCs), which reside in hypoxic tumour regions, are characterized by high tumourigenicity and chemoresistance and are often responsible for tumour progression and recurrence. Here we report a nanotherapeutic strategy to kill CSCs in tumours using nanoparticles that are co-loaded with the differentiation-inducing agent, all-trans retinoic acid, and the chemotherapeutic drug, camptothecin. All-trans retinoic acid is released under hypoxic conditions, leading to CSC differentiation in the hypoxic niche. In differentiating CSC, the reactive oxygen species levels increase, which then causes the release of camptothecin and subsequent cell death. This dual strategy enables controlled drug release in CSCs and reduces stemness-related drug resistance, enhancing the chemotherapeutic response. In breast tumour mouse models, treatment with the nanoparticles suppresses tumour growth and prevents post-surgical tumour relapse and metastasis.

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Fig. 1: Schematic of a convergent nanotherapeutic strategy to overcome intratumour heterogeneity-imposed therapeutic obstacle for enhanced anticancer efficacy.
Fig. 2: Enhanced chemo-cytotoxicity against CSCs by ATRA-induced differentiation.
Fig. 3: Preparation and characterization of ATRA/CPT-NPs.
Fig. 4: Combination effects of ATRA/CPT-NPs on reducing stemness-related properties, relieving tumour hypoxia, inhibiting cell proliferation in vitro and suppressing tumour formation in vivo.
Fig. 5: Combination effects in vivo of ATRA/CPT-NPs on inhibiting primary tumour growth.
Fig. 6: Combination effects in vivo of ATRA/CPT-NPs on inhibiting post-surgical tumour recurrence and metastasis.

Data availability

The data that support the plots within this paper and other findings of this study are available from the corresponding author upon reasonable request.


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This work was supported by the National Natural Science Foundation of China (81673381), the National Ten Thousand Talents Program for Young Top-notch Talents, the Fok Ying-Tong Education Foundation for Young Teachers in the Higher Education Institutions of China (171028), the Project of State Key Laboratory of Natural Medicines of China Pharmaceutical University (SKLNMZZ202024), the Funding of Double First-Rate Discipline Innovation Team (CPU2018GF05), the Natural Science Foundation of Jiangsu Province of China for Distinguished Young Scholars (BK20150029) and the Young Elite Scientists Sponsorship Program by CAST (2015QNRC001). We also acknowledge the Public Platform of State Key Laboratory of Natural Medicines for the use of the cell culture and analytical instrumentation facilities. We thank C. Wang at Soochow University for providing 4T1-Luc cells.

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R.M. supervised and conceived the project. R.M. and S.S. designed the experiments, analysed the data and wrote the manuscript. S.S., X.X., S.L., Y.Z., H.L. and R.M. performed the experiments. C.Z. contributed to the discussion and provided relevant advice. All the authors discussed the results and commented on the manuscript.

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Correspondence to Ran Mo.

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R.M., S.S., Y.Z. and H.L. have applied for patents related to this study.

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Experimental materials, Methods, Figs. 1–36 and Table 1.

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Shen, S., Xu, X., Lin, S. et al. A nanotherapeutic strategy to overcome chemotherapeutic resistance of cancer stem-like cells. Nat. Nanotechnol. 16, 104–113 (2021). https://doi.org/10.1038/s41565-020-00793-0

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