Rheumatoid arthritis (RA) is an inflammatory disease driven by M1 macrophages via release of abundant inflammatory cytokines. Eliminating M1 macrophages or inducing their transformation into anti-inflammatory M2 macrophages is one of the key mechanisms to reduce inflammation. Here, we report protein nanotubes cross-linked microspheres (NTMs), which exhibit nanozyme-like properties. The NTMs can alleviate RA via repolarizing inflammatory macrophages from M1 to M2, and modulating the articular redox homeostasis. Redox metal-centered NTMs possess both peroxidase- and catalase-like activities, allowing them to eliminate endogenously over-expressed ROS and collaboratively generate dissolved oxygen. NTMs is biologically safe, and can be phagocytosed by macrophages and subsequent presence within the cytoplasm. In vitro, NTMs showed anti-inflammatory effects by promoting the transition of M1 macrophages towards the anti-inflammatory M2 phenotype. Most importantly, in vivo, adjuvant-induced arthritis administrated with capsaicin-loaded NTMs showed an improved cartilage structure and organized nuclei structure, which are close to healthy native cartilage. These findings demonstrate that NTMs can modulate the microenvironment of joint via the redox enzyme-mimetic strategy, and capsaicin also showed a synergistic anti-inflammatory and pain-relief effect, which in total possessed a high potential for anti-RA treatments.

Tumor hypoxia-associated drug resistance presents a major challenge for cancer chemotherapy. However, sustained delivery systems with a high loading capability of hypoxia-inducible factor-1 (HIF-1) inhibitors are still limited. Here, we developed an ultrastable iodinated oil-based Pickering emulsion (PE) to achieve locally sustained codelivery of a HIF-1 inhibitor of acriflavine and an anticancer drug of doxorubicin for tumor synergistic chemotherapy. The PE exhibited facile injectability for intratumoral administration, great radiopacity for in vivo examination, excellent physical stability (>1 mo), and long-term sustained release capability of both hydrophilic drugs (i.e., acriflavine and doxorubicin). We found that the codelivery of acriflavine and doxorubicin from the PE promoted the local accumulation and retention of both drugs using an acellular liver organ model and demonstrated significant inhibition of tumor growth in a 4T1 tumor-bearing mouse model, improving the chemotherapeutic efficacy through the synergistic effects of direct cytotoxicity with the functional suppression of HIF-1 pathways of tumor cells. Such an iodinated oil-based PE provides a great injectable sustained delivery platform of hydrophilic drugs for locoregional chemotherapy.