Supramolecular Micelleplex Co‐Delivers Bcl‐2 siRNA and Paclitaxel for Synergistic Chemo‐Gene Cancer Therapy

Abstract Combined chemotherapy (CT) and gene therapy (GT) represent a reliable modality toward drug‐resistant tumor treatment. Yet, physical‐chemical differences between chemodrugs and nucleic acids often hinder the construction of feasible delivery systems with synergistic activity. Herein, a smart supramolecular polymeric scaffold is reported to co‐load chemodrug paclitaxel (PTX) and Bcl‐2 small interfering RNA (siRNA), respectively via Hydrogen‐bonding (H‐bonding) association and electrostatic interaction, toward efficiently reversing drug resistance and significantly inhibiting tumor growth in a synergistic manner via GT‐enhanced CT. Therefore, a cationic copolymer carrier, P(OEGA‐ co ‐DMAEA)‐ b ‐P(HFA‐ co ‐TU) (e.g., PODHT), serves as a structurally distinct drug‐delivery platform. The hydrophobic section, P(HFA‐ co ‐TU) (poly((heptafluorobutyl acrylate)‐ co ‐acylthiourea)), incorporates pendant thiourea (TU) moieties that can selectively recognize hydrophobic PTX. Such molecular recognition and co‐assembly are governed by TU/PTX double H‐bonding association in concert with hydrophobic interactions. Moreover, the cationic shell consisting of P(OEGA‐ co ‐DMAEA) (poly(oligo(ethylene glycol) monomethyl ether acrylate‐ co ‐2‐dimethylaminoethyl acrylate)) from resulting PTX‐loaded micelles can steadily bind the negative siRNA via electrostatic interaction, finally to afford the targeted supramolecular micelleplexes PTX@PODHT/siRNA. Such nanoplatform not only possesses the enhanced co‐loading capacity and transportation stability of distinct PTX and siRNA, but also can induce pH‐responsive cargos release within the tumor zone, ultimately effectively inhibiting tumor growth via synergistic CT/GT.