Although co-delivery of small-molecule drugs and siRNAs is a promising platform strategy for combination therapy, current delivery systems fail to achieve efficient endosomal escape, limiting cytosolic siRNA bioavailability and therapeutic efficacy. Conventional lipid nanoparticles (LNPs) can co-encapsulate chemotherapeutics and siRNA, but their poor endosomal escape results in suboptimal siRNA bioavailability. Here, we report a novel type of sphere-like nanoparticle (SNP) platform for co-delivery of siRNA and small-molecule drugs that overcomes these limitations. In this system, doxorubicin (DOX) is intercalated within a Janus base nanotube (JBNt) structure, while siRNA is encapsulated through electrostatic interactions, enabling stable co-packaging. Notably, SNPs exhibit significantly enhanced endosomal escape compared with lipid nanoparticles, leveraging JBNt's endosomal escape, attributable to its distinct proton-sponge-mediated buffer capacity, consequently promoting efficient, coordinated cytosolic delivery of both cargos. In a proof-of-concept study, SNP-mediated co-delivery of Multidrug Resistance 1 gene (MDR1/ABCB1)-targeting siRNA and DOX was associated with effective gene silencing and enhanced apoptosis in cancer cells, tumor spheroids, and murine ovarian tumor xenograft models. Collectively, these findings deliver proof-of-concept evidence for SNPs as a promising co-delivery platform for RNA and chemotherapeutics to overcome chemoresistance and improve anticancer efficacy.
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