Lipid nanoparticle co-delivery of siRNA silencing P-glycoprotein overcomes Camptothecin resistance in an acute lymphoblastic leukemia model

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a critical barrier to effective chemotherapy in acute lymphoblastic leukemia (ALL). Camptothecin (CPT), a potent topoisomerase I inhibitor, is a known P-gp substrate, and its rapid efflux limits intracellular retention and antitumor efficacy. Here, we report a co-delivery nanoplatform that integrates P-gp-silencing siRNA with CPT delivery to overcome MDR. Incorporating the FDA-approved ionizable lipid DLin-MC3-DMA into our phospholipid-derived CPT nanovesicle (Camptothesome) yielded a stable siRNA-loaded lipid nanoparticle (siRNA P-gp /LNP-CPT) with efficient siRNA encapsulation. In CPT-resistant CEM/C1 ALL cells, P-gp knockdown markedly increased intracellular CPT accumulation, enhanced apoptosis, and produced superior cytotoxicity compared to LNP-CPT alone. In vivo , siRNA P-gp /LNP-CPT achieved greater tumor accumulation, prolonged retention, and potent antitumor activity in CEM/C1-bearing SCID/NOD mice, with no significant systemic toxicity or CPT-associated gastrointestinal injury. These findings demonstrate that co-delivering P-gp-targeting siRNA and CPT in a single nanocarrier effectively circumvents P-gp-mediated drug efflux, offering a promising strategy for unlocking the therapeutic potential of CPT for treating MDR leukemia and other refractory malignancies.