The combination of chemotherapy and immunotherapy motivates a potent immune system by triggering immunogenic cell death (ICD), showing great potential in inhibiting tumor growth and improving the immunosuppressive tumor microenvironment (ITM). However, the therapeutic effectiveness has been restricted by inferior drug bioavailability. Herein, we reported a universal bioresponsive doxorubicin (DOX)-based nanogel to achieve tumor-specific co-delivery of drugs. DOX-based mannose nanogels (DM NGs) was designed and choosed as an example to elucidate the mechanism of combined chemo-immunotherapy. As expected, the DM NGs exhibited prominent micellar stability, selective drug release and prolonged survival time, benefited from the enhanced tumor permeability and prolonged blood circulation. We discovered that the DOX delivered by DM NGs could induce powerful anti-tumor immune response facilitated by promoting ICD. Meanwhile, the released mannose from DM NGs was proved as a powerful and synergetic treatment for breast cancer in vitro and in vivo, via damaging the glucose metabolism in glycolysis and the tricarboxylic acid cycle. Overall, the regulation of tumor microenvironment with DOX-based nanogel is expected to be an effectual candidate strategy to overcome the current limitations of ICD-based immunotherapy, offering a paradigm for the exploitation of immunomodulatory nanomedicines.

UNASSIGNED: Tendon tissue engineering requires scaffold-free techniques for safe and long-term clinical applications and to explore alternative cell sources to tenocytes. Therefore, we histologically assessed tendon formation in a scaffold-free Bio-three-dimensional (3D) construct developed from normal human dermal fibroblasts (NHDFs) using our Bio-3D printer system under tensile culture in vitro.
UNASSIGNED: Scaffold-free ring-like tissues were constructed from 120 multicellular spheroids comprising NHDFs using a bio-3D printer. Ring-like tissues were cultured in vitro under static tensile-loading with or without in-house tensile devices (tension-loaded and tension-free groups), with increases in tensile strength applied weekly to the tensile-loaded group. After a 4 or 8-week culture on the device, we evaluated histological findings according to tendon-maturing score and immunohistological findings of the middle portion of the tissues for both groups (n = 4, respectively).
UNASSIGNED: Histology of the tension-loaded group revealed longitudinally aligned collagen fibers with increased collagen deposition and spindle-shaped cells with prolonged culture. By contrast, the tension-free group showed no organized cell arrangement or collagen fiber structure. Additionally, the tension-loaded group showed a significantly improved tendon-maturing score as compared with that for the tension-free group at week 8. Moreover, immunohistochemistry revealed tenascin C distribution with a parallel arrangement in the tensile-loading direction at week 8 in the tension-loaded group, which exhibited stronger scleraxis-staining intensity than that observed in the tension-free group at weeks 4 and 8.
UNASSIGNED: The NHDF-generated scaffold-free Bio-3D construct underwent remodeling and formed tendon-like structures under tensile culture in vitro.