Cancer cell membrane-biomimetic and antioxidant-powered nanoplatform for overcoming multidrug resistance in triple-negative breast cancer

  • Int J Biol Macromol. 2025 Dec 6;337(Pt 1):149478. doi: 10.1016/j.ijbiomac.2025.149478.
Qi Sun  1 ,  Xinhao Jin  2 ,  Yitong Ma  2 ,  Xi Li  2 ,  Mengqi Peng  2 ,  Shamuhaer Yelebolati  2 ,  Chunying Cui  3
Affiliations
  • 1. Department of Pharmaceutics, School of Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, PR China; Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Beijing, 100069, PR China; Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing, 100069, PR China; Beijing Laboratory of Biomedical Materials, Beijing, 100069, PR China; Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, PR China. Electronic address: [email protected].
  • 2. Department of Pharmaceutics, School of Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, PR China; Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Beijing, 100069, PR China; Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing, 100069, PR China; Beijing Laboratory of Biomedical Materials, Beijing, 100069, PR China; Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, PR China.
  • 3. Department of Pharmaceutics, School of Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, PR China; Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Beijing, 100069, PR China; Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing, 100069, PR China; Beijing Laboratory of Biomedical Materials, Beijing, 100069, PR China; Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, PR China. Electronic address: [email protected].
PMID: 41360238 DOI: 10.1016/j.ijbiomac.2025.149478
Abstract

Triple-negative breast Cancer (TNBC) is notoriously refractory to chemotherapy because of multidrug resistance (MDR) driven by P-glycoprotein (P-gp) overexpression and oxidative stress in microenvironment (TME). To overcome this, we engineered a triple-action biomimetic nanoplatform (BSA-OPC/siMDR1@CCM) co-encapsulating oligomeric proanthocyanidins (OPC) and MDR1-targeting siRNA (siMDR1) within Cancer cell membrane (CCM) cloaked bovine serum albumin (BSA) nanoparticles. The precision-engineered nanoplatform achieved >89 % OPC encapsulation efficiency, complete siMDR1 complexation, pH-responsive drug release (26 % at tumor-mimetic pH 6.5 vs <5 % at systemic pH 7.4), and robust nuclease resistance. In vitro, enhanced cellular uptake and enabled lysosomal escape, achieving 65 % MDR1 knockdown and 85 % ROS suppression to synergistically restore doxorubicin (DOX) sensitivity. In vivo, the nanoplatform showed 7.7-fold greater tumor accumulation versus controls, driving 68 % tumor regression and 100 % 30-day survival in MDR-4T1 models while abolishing metastases. Mechanistic studies confirmed downregulation of P-gp, p53, Ki67, HIF-1α, and ROS without systemic toxicity. This integrated strategy combining targeted delivery, genetic resistance reversal, and microenvironment remodeling, represents a potential strategy against chemorefractory TNBC.

Keywords
Antioxidant; Biomimetic nanoplatforms; Multidrug resistance; Oligomeric proanthocyanidins; Triple-negative breast cancer; siMDR1.
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