ROS-responsive supramolecular hydrogel system for the controlled release of oncolytic adenovirus and paclitaxel in cancer therapy

The synergistic combination of oncolytic adenovirus (oAd) and paclitaxel chemodrug holds great potential for cancer therapy as it can enhance cell apoptosis, the viral replication in cancer cells, and induce a potent antitumor effect. However, clinical output is insufficient because of the rapid blood clearance and inactivation of viral activity within high-reactive oxygen species (ROS) tumor microenvironment (TME). In this regard, we have developed an ROS responsive supramolecular hydrogel (mPEG-b-PCL-DPMP/α-cyclodextrin (DPMP/α-CD hydrogel)) system to protect oAd bioactivity while providing sustained, localized co-delivery of paclitaxel (PTX). The amount of ROS was evaluated by fluorescence measurements using H₂DCFDA as a probe and confirmed that there was a significant decrease in ROS level by DPMP/α-CD hydrogel. An in vivo degradation study showed that the hydrogel underwent substantial degradation within one week. Furthermore, oAd and PTX encapsulated in DPMP/α-CD hydrogel were released consistently and retained the viral activity, exhibiting cancer cell killing efficacy under strong tumor microenvironment conditions. In vivo, a single intratumoral injection formed a stable depot that persisted for over a week, leading to superior tumor regression in H460 xenograft models compared to naked oAd or PTX alone. Histological and biochemical analyses confirmed no detectable histopathological abnormalities in the examined major organs or elevations in the measured serum liver and kidney injury markers under the conditions evaluated. Altogether, this ROS-responsive shield-and-release injectable supramolecular hydrogel platform loaded with oAd/PTX exhibits downregulated ROS level at tumor microenvironment and enhanced anti-tumor effect. STATEMENT OF SIGNIFICANCE: • An active shield-scavenge-release hydrogel was engineered to enhance oncolytic adenovirus/paclitaxel (oAd/PTX) combination therapy. • The hydrogel protects oxidation-sensitive adenovirus while enabling sustained local viral release. • ROS-responsive dipentaerythritol hexakis(3-mercaptopropionate) (DPMP) segments convert the oxidative tumor microenvironment into a therapeutic release trigger. • PTX-loaded hydrophobic domains support prolonged chemotherapy without disrupting hydrogel architecture. • Sustained oAd/PTX co-release amplifies viral replication, tumor cell killing, and antitumor efficacy. • A single intratumoral administration achieves durable tumor suppression with minimal systemic toxicity.