Carrier‐Free Berberine/Nitidine Chloride Self‐Assembled Nanoparticles Induce Ferroptosis to Overcome Bortezomib Resistance in Multiple Myeloma

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 Fe 2+ 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.