In Situ shRNA Synthesis on DNA–Polylactide Nanoparticles to Treat Multidrug Resistant Breast Cancer

Abstract

Nanomedicine has shown unprecedented potential for cancer theranostics. Nucleic acid (e.g., DNA and RNA) nanomedicines are of particular interest for combination therapy with chemotherapeutics. However, current nanotechnologies to construct such nucleic acid nanomedicines, which rely on chemical conjugation or physical complexation of nucleic acids with chemotherapeutics, have restrained their clinical translation due to limitations such as low drug loading efficiency and poor biostability. Herein, in situ rolling circle transcription (RCT) is applied to synthesize short hairpin RNA (shRNA) on amphiphilic DNA–polylactide (PLA) micelles. Core–shell PLA@poly-shRNA structures that codeliver a high payload of doxorubicin (Dox) and multidrug resistance protein 1 (MDR1) targeted shRNA for MDR breast cancer (BC) therapy are developed. DNA–PLA conjugates are first synthesized, which then self-assemble into amphiphilic DNA–PLA micelles; next, using the conjugated DNA as a promoter, poly-shRNA is synthesized on DNA–PLA micelles via RCT, generating PLA@poly-shRNA microflowers; and finally, microflowers are electrostatically condensed into nanoparticles using biocompatible and multifunctional poly(ethylene glycol)-grafted polypeptides (PPT-g-PEG). These PLA@poly-shRNA@PPT-g-PEG nanoparticles are efficiently delivered into MDR breast cancer cells and accumulated in xenograft tumors, leading to MDR1 silencing, intracellular Dox accumulation, potentiated apoptosis, and enhanced tumor therapeutic efficacy. Overall, this nanomedicine platform is promising to codeliver anticancer nucleic acid therapeutics and chemotherapeutics.

Herein, an nucleic acid nanomedicine is reported using in situ synthesis of shRNA (short hairpin RNA) on DNA-polyactide micelles for co-delivery of multi-drug resistance protein 1 (MDR1)-silencing shRNA and chemotherapeutics, which is then condensed by a polypeptide copolymer. The resulting nanoparticles abrogate drug resistance, enhance cellular accumulation of doxorubicin, and inhibit tumor growth in an MDR breast cancer model.

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