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

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.