Tumor microenvironment-responsive hyaluronate-calcium carbonate hybrid nanoparticle enables effective chemo-therapy for primary and advanced osteosarcomas

Osteosarcoma is the most common malignancy in the bone. Current chemotherapy offers limited efficacy with significant side effects, especially for advanced and relapsed osteosarcomas. Nanoparticle-formulated chemotherapeutic drugs may be used to resolve these issues, but several aspects of these formulations remain unsatisfactory, such as how to improve their stability in the bloodstream, prevent undesirable drug leakage, and enhance targeted drug accumulation in the tumor. In this study, a tumor microenvironment-responsive calcium carbonate （CaCO3）- crosslinked hyaluronate （HA） nanopartide was prepared via a ＂green＂ process to effectively deliver doxorubicin （DOX） for the treatment of various stages of osteosarcoma. The DOX-loaded hyaluronate-calcium carbonate hybrid nanoparfide （HA-DOX/CaCO3） demonstrated superior stability both in vitro and in vivo, and rapidly released DOX at the tumor site when triggered by the acidic tumor microenvironment. Compared with free DOX and a non-crosslinked nanoparficle （HA-DOX）, HA-DOX]CaCO3 exhibited the most potent inhibition efficacy toward both primary and advanced models of routine osteosarcoma, resulting in effective tumor inhibition, improved survival time, and reduced adverse effects. Most importantly, in the advanced osteosarcoma model, HA-DOX/CaCO3 potently suppressed tumor growth by 84.6%, which indicates the potential of this platform for osteosarcoma treatment, particularly for advanced and relapsed cases. The proposed polysaccharide nanopartide would be a promising drug delivery platform to advance osteosarcoma nanomedicine.

Stem cell-derived hepatocyte therapy using versatile biomimetic nanozyme incorporated nanofiber-reinforced decellularized extracellular matrix hydrogels for the treatment of acute liver failure

Reactive oxygen species(ROS)-associated oxidative stress,inflammation storm,and massive hepatocyte necrosis are the typical manifestations of acute liver failure(ALF),therefore specific therapeutic interventions are essential for the devastating disease.Here,we developed a platform consisting of versatile biomimetic copper oxide nanozymes(Cu NZs)-loaded PLGA nanofibers(Cu NZs@PLGA nanofibers)and decellularized extracellular matrix(dECM)hydrogels for delivery of human adipose-derived mesenchymal stem/stromal cells-derived hepatocyte-like cells(hADMSCs-derived HLCs)(HLCs/Cu NZs@fiber/dECM).Cu NZs@PLGA nanofibers could conspicuously scavenge excessive ROS at the early stage of ALF,and reduce the massive accumulation of pro-inflammatory cytokines,herein efficiently preventing the deterioration of hepatocytes necrosis.Moreover,Cu NZs@PLGA nanofibers also exhibited a cytoprotection effect on the transplanted HLCs.Meanwhile,HLCs with hepatic-specific biofunctions and anti-inflammatory activity acted as a promising alternative cell source for ALF therapy.The dECM hydrogels further provided the desirable 3D environment and favorably improved the hepatic functions of HLCs.In addition,the pro-angiogenesis activity of Cu NZs@PLGA nanofibers also facilitated the integration of the whole implant with the host liver.Hence,HLCs/Cu NZs@fiber/dECM performed excellent synergistic therapeutic efficacy on ALF mice.This strategy using Cu NZs@PLGA nanofiber-reinforced dECM hydrogels for HLCs in situ delivery is a promising approach for ALF therapy and shows great potential for clinical translation.