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A long-standing paucity of effective therapies results in the poor outcomes of triple-negative breast cancer brain metastases. Immunotherapy has made progress in the treatment of tumors, but limited by the non-immunogenicity of tumors and strong immunosuppressive environment, patients with TNBC brain metastases have not yet benefited from immunotherapy. Dual immunoregulatory strategies with enhanced immune activation and reversal of the immunosuppressive microenvironment provide new therapeutic options for patients. Here, we propose a cocktail-like therapeutic strategy of microenvironment regulation-chemotherapy-immune synergistic sensitization and construct reduction-sensitive immune microenvironment regulation nanomaterials (SIL@T). SIL@T modified with targeting peptide penetrates the BBB and is subsequently internalized into metastatic breast cancer cells, releasing silybin and oxaliplatin responsively in the cells. SIL@T preferentially accumulates at the metastatic site and can significantly prolong the survival period of model animals. Mechanistic studies have shown that SIL@T can effectively induce immunogenic cell death of metastatic cells, activate immune responses and increase infiltration of CD8+ T cells. Meanwhile, the activation of STAT3 in the metastatic foci is attenuated and the immunosuppressive microenvironment is reversed. This study demonstrates that SIL@T with dual immunomodulatory functions provides a promising immune synergistic therapy strategy for breast cancer brain metastases.

Regeneration of diabetic bone defects remains a formidable challenge due to the chronic hyperglycemic state, which triggers the accumulation of advanced glycation end products (AGEs) and reactive oxygen species (ROS). To address this issue, we have engineered a bimetallic metal-organic framework-derived Mn@Co 3 O 4 @Pt nanoenzyme loaded with alendronate and Mg 2+ ions (termed MCPtA) to regulate the hyperglycemic microenvironment and recover the osteogenesis/osteoclast homeostasis. Notably, the Mn atom substitution in the Co 3 O 4 nanocrystalline structure could modulate the electronic structure and significantly improve the SOD/CAT catalytic activity for ROS scavenging. By integration with GOx-like Pt nanoparticles, the MCPtA achieved effective multiple cascade catalytic performance that facilitated the clearance of glucose and ROS. Furthermore, the MCPtA was encapsulated within a glucose-responsive hydrogel cross-linked via a borate ester bond, termed PAM, to evaluate the potential of the composite hydrogel for cranial defect repair in diabetic rats. The in vitro/vivo experiments as well as the RNA sequencing analysis demonstrated that the nanoenzyme composite hydrogel could disrupt the glucose-ROS-induced inflammation and promoted osteogenesis and angiogenesis, in consequence, improving the therapeutic effects for diabetic bone regeneration. This study provided crucial insights into nanoenzyme-mediated microenvironmental regulation for diabetic bone regeneration.

Covalent organic frameworks (COFs) has been attracted lots of interest and now are considered as one of the most promising materials in the field of H 2 O 2 photosynthesis science 2020, indicating that it has become an emerging hot field. Therefore, a timely and comprehensive review of this topic to promote further development is highly desirable, especially in terms of the microenvironmental relationship between structural design and performance. In view of this, the Review summarizes the recent research progress with a focus on the impact of microenvironmental changes in COFs on the performance of H 2 O 2 photosynthsis, and discusses the current research status, critical challenges, possible future directions. In addition, this Review will deepen the comprehension of microenvironmental regulation and provide inspiration and feasibility for the design and application of COFs-based materials. [Display omitted] • The research progress of COFs used for generating H 2 O 2 were summarized. • The impact of microenvironmental changes in COFs on H 2 O 2 production was elucidated. • The critical challenges and possible future directions for H 2 O 2 were clarified. • This will provide guidance for constructing COFs with effective H 2 O 2 photosynthesis. Hydrogen peroxide (H 2 O 2), as a green liquid energy source, has shown promising potential in multiple fields. The covalent organic frameworks (COFs) have leaped the photocatalytic production of H 2 O 2 since 2020 due to their controllable construction units and abundant active sites. Here, we describe the latest research progress in COFs based photocatalysts for H 2 O 2 photosynthesis. Then, focusing on the impact of microenvironmental changes in building units on the performance of H 2 O 2 , the construction strategies for improving the efficiency of COFs photocatalytic H 2 O 2 production was summarized, and the development ideas of COFs in the field of H 2 O 2 photosynthesis were prospected. Through comparative evaluation, this Review aims to clarify the current research status, critical challenges, and possible future directions, which will undoubtedly stimulate innovative ideas in designing photocatalysts for efficient production of H 2 O 2. In addition, this timely Review will give insight into the COFs with microenvironmental regulation more comprehensively and provide a novel perspective for effectively improving the efficiency of H 2 O 2 photosynthesis. [ABSTRACT FROM AUTHOR]

A bstract Restoration of extensive bone loss and defects remain as an unfulfilled challenge in modern medicine. Given the critical contributions to bone homeostasis and diseases, mesenchymal stem cells (MSCs) have shown great promise to jumpstart and facilitate bone healing, with immense regenerative potential in both pharmacology-based endogenous MSC rescue/mobilization in skeletal diseases and emerging application of MSC transplantation in bone tissue engineering and cytotherapy. However, efficacy of MSC-based bone regeneration was not always achieved; particularly, fulfillment of MSC-mediated bone healing in diseased microenvironments of host comorbidities remains as a major challenge. Indeed, impacts of diseased microenvironments on MSC function rely not only on the dynamic regulation of resident MSCs by surrounding niche to convoy pathological signals of bone, but also on the profound interplay between transplanted MSCs and recipient components that mediates and modulates therapeutic effects on skeletal conditions. Accordingly, novel solutions have recently been developed, including improving resistance of MSCs to diseased microenvironments, recreating beneficial microenvironments to guarantee MSC-based regeneration, and usage of subcellular vesicles of MSCs in cell-free therapies. In this review, we summarize state-of-the-art knowledge regarding applications and challenges of MSC-mediated bone healing, further offering principles and effective strategies to optimize MSC-based bone regeneration in aging and diseases. [ABSTRACT FROM AUTHOR]

A long-standing paucity of effective therapies results in the poor outcomes of triple-negative breast cancer brain metastases. Immunotherapy has made progress in the treatment of tumors, but limited by the non-immunogenicity of tumors and strong immunosuppressive environment, patients with TNBC brain metastases have not yet benefited from immunotherapy. Dual immunoregulatory strategies with enhanced immune activation and reversal of the immunosuppressive microenvironment provide new therapeutic options for patients. Here, we propose a cocktail-like therapeutic strategy of microenvironment regulation-chemotherapy-immune synergistic sensitization and construct reduction-sensitive immune microenvironment regulation nanomaterials (SIL@T). SIL@T modified with targeting peptide penetrates the BBB and is subsequently internalized into metastatic breast cancer cells, releasing silybin and oxaliplatin responsively in the cells. SIL@T preferentially accumulates at the metastatic site and can significantly prolong the survival period of model animals. Mechanistic studies have shown that SIL@T can effectively induce immunogenic cell death of metastatic cells, activate immune responses and increase infiltration of CD8 + T cells. Meanwhile, the activation of STAT3 in the metastatic foci is attenuated and the immunosuppressive microenvironment is reversed. This study demonstrates that SIL@T with dual immunomodulatory functions provides a promising immune synergistic therapy strategy for breast cancer brain metastases., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)