Carrier‐Free Berberine/Nitidine Chloride Self‐Assembled Nanoparticles Induce Ferroptosis to Overcome Bortezomib Resistance in Multiple Myeloma
4 affiliations
- 1The First Affiliated Hospital of Guangzhou University of Chinese Medicine Guangzhou People's Republic of China
- 2The Affiliated Guangdong Second Provincial General Hospital of Jinan University Guangzhou Guangdong People's Republic of China
- 3Key Laboratory of Regenerative Medicine of Ministry of Education Guangzhou Guangdong People's Republic of China
- 4Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research College of Pharmacy Jinan University Guangzhou People's Republic of China
Abstract
Therapeutic relapse driven by bortezomib resistance represents a formidable clinical barrier in the management of multiple myeloma (MM). Here, a carrier‐free, supramolecular nanoplatform was engineered through the spontaneous co‐assembly of two natural alkaloids, berberine (BBR) and nitidine chloride (NC), termed BBR/NC‐SAPs, to counter this malignancy. Driven by cooperative π‐π stacking and van der Waals forces, BBR/NC‐SAPs display superior anti‐MM efficacy and optimized biosafety as compared to the free‐drug combination. Quantitative proteomics and functional landscapes showed that BBR/NC‐SAPs robustly activate iron‐dependent ferroptosis, as evidenced by massive lipid peroxidation, intracellular Fe2+ overload, and mitochondrial depolarization. Mechanistically, integrated target deconvolution and atomistic molecular modeling identified NR2F2 as a direct target of BBR/NC‐SAPs. Functional knock‐out and rescue evaluations definitively validated that NR2F2 is an essential mediator governing the therapeutic response, as NR2F2 depletion occluded the ferroptotic cascade, and lentiviral reconstitution fully restored cellular sensitivity and GPX4‐associated ferroptosis activation. Further, BBR/NC‐SAPs markedly suppressed tumor growth and prolonged survival in bortezomib‐resistant MM xenograft models, a therapeutic benefit actively reversed by the ferroptosis inhibitor ferrostatin‐1. Collectively, this work highlights a paradigm of natural product‐derived nanotechnology that targets the NR2F2–GPX4 axis, offering a promising supramolecular strategy to overcome drug resistance in refractory hematological tumors.
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BibTeX
@article{lv2026carrierfree,
title = {{Carrier‐Free Berberine/Nitidine Chloride Self‐Assembled Nanoparticles Induce Ferroptosis to Overcome Bortezomib Resistance in Multiple Myeloma}},
author = {Yiwen Lv and Shuang Liu and Hong Wu and Guiluan Li and Ying Rong and Guangchao Li and Yangmin Zhu and Qi Zhong and Ruiming Ou and Huijuan Shen and Zhi Liu and Jing Huang and Zhenwei Wang and Pei Lin and Qing Zhang and Guopan Yu and Zhao Yin},
journal = {Advanced Science},
year = {2026},
month = aug,
doi = {10.1002/advs.77174},
url = {https://doi.org/10.1002/advs.77174},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Carrier‐Free Berberine/Nitidine Chloride Self‐Assembled Nanoparticles Induce Ferroptosis to Overcome Bortezomib Resistance in Multiple Myeloma
AU - Yiwen Lv
AU - Shuang Liu
AU - Hong Wu
AU - Guiluan Li
AU - Ying Rong
AU - Guangchao Li
AU - Yangmin Zhu
AU - Qi Zhong
AU - Ruiming Ou
AU - Huijuan Shen
AU - Zhi Liu
AU - Jing Huang
AU - Zhenwei Wang
AU - Pei Lin
AU - Qing Zhang
AU - Guopan Yu
AU - Zhao Yin
PY - 2026
DA - 2026/08/18
JO - Advanced Science
DO - 10.1002/advs.77174
UR - https://doi.org/10.1002/advs.77174
AB - Therapeutic relapse driven by bortezomib resistance represents a formidable clinical barrier in the management of multiple myeloma (MM). Here, a carrier‐free, supramolecular nanoplatform was engineered through the spontaneous co‐assembly of two natural alkaloids, berberine (BBR) and nitidine chloride (NC), termed BBR/NC‐SAPs, to counter this malignancy. Driven by cooperative π‐π stacking and van der Waals forces, BBR/NC‐SAPs display superior anti‐MM efficacy and optimized biosafety as compared to the free‐drug combination. Quantitative proteomics and functional landscapes showed that BBR/NC‐SAPs robustly activate iron‐dependent ferroptosis, as evidenced by massive lipid peroxidation, intracellular Fe2+ overload, and mitochondrial depolarization. Mechanistically, integrated target deconvolution and atomistic molecular modeling identified NR2F2 as a direct target of BBR/NC‐SAPs. Functional knock‐out and rescue evaluations definitively validated that NR2F2 is an essential mediator governing the therapeutic response, as NR2F2 depletion occluded the ferroptotic cascade, and lentiviral reconstitution fully restored cellular sensitivity and GPX4‐associated ferroptosis activation. Further, BBR/NC‐SAPs markedly suppressed tumor growth and prolonged survival in bortezomib‐resistant MM xenograft models, a therapeutic benefit actively reversed by the ferroptosis inhibitor ferrostatin‐1. Collectively, this work highlights a paradigm of natural product‐derived nanotechnology that targets the NR2F2–GPX4 axis, offering a promising supramolecular strategy to overcome drug resistance in refractory hematological tumors.
SN - 2198-3844
ER -