Carboxymethylated Alginate-Resiquimod Micelles Reverse the Immunosuppressive Tumor Microenvironment and Synergistically Enhance the Chemotherapy and Immunotherapy for Gastric Cancer.

Due to the intrinsic weak immunogenicity of tumor cells and the quantitatively and functionally different populations of immune cells, immunosuppression has become the major obstacle for cancer immunotherapy. In this study, the biocompatible alginate was chemically modified with the carboxyethyl linker to facilitate the esterification reaction of the resultant carboxymethylated alginate (CMA) and resiquimod (R848), the agonist of Toll-like receptor 7/8 (TLR7/8a). In aqueous solution, the hydrophilic CMA and the hydrophobic R848 formed stable nanomicelles (CMA-R848) by self-assembling. After combined administration of CMA-R848 and cisplatin (Cis) in a gastric cancer (GC) model, the long-circulating CMA-R848 micelle reached the mild acidic tumor microenvironment (TME); the ester bonds were quickly cleaved by the ubiquitous esterase and released the single molecule of R848. In vitro and in vivo results demonstrated that the released R848 efficiently promoted co-stimulatory molecules' expression of dendritic cells (DCs), enhanced the antigen uptake and cross-presentation, and primed the cytotoxic T lymphocytes' (CTLs) infiltration and killing effects, thereby reprogramming the "cold tumor" into the "hot tumor". In addition, the ex vivo tumor sections revealed that the released R848 effectively repolarized the M2-like tumor-associated macrophages (TAMs) into M1-like macrophages, exerted synergistic antitumor activity, reduced the tumor burden, and prolonged the overall survival duration of the GC animal model. Our study provided a targeting therapeutic strategy overcoming the limitations of R848 in vivo, and enhanced the efficacy of GC chemotherapy and immunotherapy by TME modulation.

Auxetic Black Phosphorus: A 2D Material with Negative Poisson's Ratio.

The Poisson's ratio of a material characterizes its response to uniaxial strain. Materials normally possess a positive Poisson's ratio - they contract laterally when stretched, and expand laterally when compressed. A negative Poisson's ratio is theoretically permissible but has not, with few exceptions of man-made bulk structures, been experimentally observed in any natural materials. Here, we show that the negative Poisson's ratio exists in the low-dimensional natural material black phosphorus and that our experimental observations are consistent with first-principles simulations. Through applying uniaxial strain along armchair direction, we have succeeded in demonstrating a cross-plane interlayer negative Poisson's ratio on black phosphorus for the first time. Meanwhile, our results support the existence of a cross-plane intralayer negative Poisson's ratio in the constituent phosphorene layers under uniaxial deformation along the zigzag axis, which is in line with a previous theoretical prediction. The phenomenon originates from the puckered structure of its in-plane lattice, together with coupled hinge-like bonding configurations.