Breaking-Down Tumoral Physical Barrier by Remotely Unwrapping Metal-Polyphenol-Packaged Hyaluronidase for Optimizing Photothermal/Photodynamic Therapy-Induced Immune Response.

The therapy of solid tumors is often hindered by the compact and rigid tumoral extracellular matrix (TECM). Precise reduction of TECM by hyaluronidase (HAase) in combination with nanotechnology is promising for solid tumor therapeutics, yet remains an enormous challenge. Inspired by the treatment of iron poisoning, here a remotely unwrapping strategy is proposed of metal-polyphenol-packaged HAase (named PPFH) by sequentially injecting PPFH and a clinically used iron-chelator deferoxamine (DFO). The in situ dynamic disassembly of PPFH can be triggered by the intravenously injected DFO, resulting in the release, reactivation, and deep penetration of encapsulated HAase inside tumors. Such a cost-effective HAase delivery strategy memorably improves the subsequent photothermal and photodynamic therapy (PTT/PDT)-induced intratumoral infiltration of cytotoxic T lymphocyte cells and the cross-talk between tumor and tumor-draining lymph nodes (TDLN), thereby decreasing the immunosuppression and optimizing tumoricidal immune response that can efficiently protect mice from tumor growth, metastasis, and recurrence in multiple mouse cancer models. Overall, this work presents a proof-of-concept of the dynamic disassembly of metal-polyphenol nanoparticles for extracellular drug delivery as well as the modulation of TECM and immunosuppressive tumor microenvironment.

Drug in Therapeutic Polymer: Sinomenine-Loaded Oxidation-Responsive Polymeric Nanoparticles for Rheumatoid Arthritis Treatment.

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that frequently involves cartilage damage and the destruction of the bone structure, ultimately resulting in disability and long-term pain. It is clear that overexpression of reactive oxygen species (ROS) and the complex inflammatory microenvironment are the main causes of RA pathogenesis; thereby, the efficacy of any single-drug treatment is limited. Herein, we formulated a therapeutic hyaluronic acid derivative (PAM-HA) with adsorption capacity to the subchondral bone, a long retention time within inflamed joints, and ROS-scavenging capacity, which was used as a drug carrier for realizing the controlled release of sinomenine (Sin) within arthritic joints. This "drug in therapeutic polymer" design strategy was aimed at realizing antioxidant and anti-inflammatory combination therapy for RA. In vivo experiments suggest that PAM-HA@Sin NPs can be retained in the inflamed joints of rats for a long time compared with commercially available free Sin injections. As expected, therapeutic PAM-HA polymeric carriers can increase joint lubrication and reduce oxidative stress, while the released Sin induces downregulation of proinflammatory factors (TNF-α and IL-1ß) and upregulation of anti-inflammatory factors (Arg-1 and IL-10) via the NF-κB pathway. In summary, a ROS-scavenging hyaluronic acid (HA) derivative was developed as the nanocarrier for Sin delivery to simultaneously remodel the oxidative/inflammatory microenvironment in RA, which opens up new horizons for the development of therapeutic polymers and the combined therapeutic strategies.