Natural polysaccharide-small molecule smart responsive nanogels: Design, synthesis, and synergistic chemoimmunotherapy for tumors.

Cancer poses a significant medical challenge worldwide. Research into tumor biology has revealed the prevalence of acidic conditions and abnormally high levels of reactive oxygen species (ROS) within the tumor microenvironment. In response to these findings, a ROS-responsive crosslinker, (((oxalylbis(oxy))bis(methylene))bis(4,1-phenylene))diboronic acid (OBA), was designed and synthesized using (4-hydroxymethyl)phenylboronic acid and ethanedioyl chloride as reactants. pH-responsive boronate ester bonds were formed between the diboronic acid groups of the crosslinker and the dihydroxyl groups of the naturally occurring active Astragalus polysaccharide (ASP). This resulted in the successful construction of pH/ROS dual-responsive nanogels (BAI@ASPOBA) loaded with the chemotherapeutic natural small molecule baicalein (BAI). Characterization of BAI@ASPOBA through molecular dynamics simulations and other methods demonstrated that it not only inhibited the proliferation of A549 tumor cells in vitro but also exhibited remarkable anti-tumor activity in vivo, along with excellent safety and biocompatibility. Further mechanistic studies revealed that the anti-tumor activity arises from the synergistic enhancement of the chemotherapeutic effects of BAI and the natural polysaccharide ASP. Specifically, the constructed BAI@ASPOBA nanogels enhanced the anti-tumor efficacy of BAI, while ASP, serving as the carrier for the nanomaterials, played an immunostimulatory role, facilitating tumor immunotherapy. The design and development of the novel BAI@ASPOBA nanogels in this study are anticipated to provide a new and effective treatment strategy for cancer therapy.