Enhanced combination therapy through tumor microenvironment-activated cellular uptake and ROS-sensitive drug release using a dual-sensitive nanogel†

Although the co-delivery of chemotherapeutic and photodynamic agents has been studied for years, developing a simple and efficient nanoplatform for high co-delivery efficiency remains a challenge for clinical applications. In this study, we prepared a reactive oxygen species (ROS) and pH dual-sensitive nanogel for the co-encapsulation of doxorubicin (DOX) and indocyanine green (ICG)-conjugated bovine serum albumin (BSA) via a simple inverse miniemulsion polymerization process. This was followed by modification with pegylated cell-penetrating peptides (CPPs) containing citraconic anhydride (CDM) linkers, which are sensitive to weakly acidic microenvironments (pH 6.5). Pegylation endowed the nanogel with extended blood circulation, while the de-shielding of polyethylene glycol (PEG) exposed the CPPs, significantly enhancing cellular uptake. Upon near-infrared (NIR) irradiation, ROS generated by ICG not only killed tumor cells but also triggered the release of DOX through nanogel disintegration. Serial experiments verified the nanogel's high co-delivery efficiency, tumor tissue matrix microenvironment-triggered cellular uptake, controlled drug release, and synergistic antitumor effects. Therefore, this dual-sensitive nanogel, prepared via inverse miniemulsion polymerization, offers a facile approach to improving co-delivery efficiency for combination therapy.