Mitochondrial Localized In Situ Self-Assembly Reprogramming Tumor Immune and Metabolic Microenvironment for Enhanced Cancer Therapy.

The inherent immune and metabolic tumor microenvironment (TME) of most solid tumors adversely affect the antitumor efficacy of various treatments, which is an urgent issue to be solved in clinical cancer therapy. In this study, a mitochondrial localized in situ self-assembly system is constructed to remodel the TME by improving immunogenicity and disrupting the metabolic plasticity of cancer cells. The peptide-based drug delivery system can be pre-assembled into nanomicelles in vitro and form functional nanofibers on mitochondria through a cascade-responsive process involving reductive release, targeted enrichment, and in situ self-assembly. The organelle-specific in situ self-assemblyeffectively switches the role of mitophagy from pro-survival to pro-death, which finally induces intense endoplasmic reticulum stress and atypical type II immunogenic cell death. Disintegration of the mitochondrial ultrastructure also impedes the metabolic plasticity of tumor cells, which greatly promotes the immunosuppresive TME remodeling into an immunostimulatory TME. Ultimately, the mitochondrial localized in situ self-assembly system effectively suppresses tumor metastases, and converts cold tumors into hot tumors with enhanced sensitivity to radiotherapy and immune checkpoint blockade therapy. This study offers a universal strategy for spatiotemporally controlling supramolecular self-assembly on sub-organelles to determine cancer cell fate and enhance cancer therapy.

An enzyme-instructed self-assembly system induces tumor acidosis via sequential-dual effect for cancer selective therapy.

The acidosis anti-tumor therapy, based on the altered energy metabolism pathway of tumor cells, has been proposed as an attractive method for cancer selective treatment. However, the strategy of inducing tumor acidosis by using a single drug to simultaneously inhibit both lactate efflux and consumption has not been reported yet. Herein, an in situ enzyme-instructed self-assembly (EISA) system was rationally fabricated to induce tumor acidosis apoptosis for cancer selective therapy. Depending on the sequential effect of the in situ EISA system, the targeted drug was successively distributed on the membrane and intracellular, inhibiting MCT4 mediated lactate efflux and mitochondrial tricarboxylic acid (TCA) cycle mediated lactate consumption, respectively. Through the dual obstruction of lactate metabolism to trigger tumor acidosis, the in situ EISA nanomedicine showed selective growth and migration inhibition against cancer cells. In addition, the nanomedicine also displayed a radio-sensitization effect in vitro due to causing the mitochondrial dysfunction, and exhibited a prominent synergistic chemo-radiotherapy anti-tumor performance in vivo. Accordingly, this work demonstrated that the in situ EISA system could endow the LND with sequential-dual effects to induce tumor acidosis, which may provide an enlightening strategy for anticancer drug delivery and cancer selective therapy. STATEMENT OF SIGNIFICANCE: With the help of the sequential effect of in situ EISA , the serial attack of LND against different targets was effectively realized to induce tumor acidosis and combined chemo-radiotherapy, implying the importance of the relationship between structure and function, which could offer a distinctive inspiration for future drug delivery system design and anti-tumor application.

Gut microbiota community characteristics and disease-related microorganism pattern in a population of healthy Chinese people.

China's population accounts for about 1/5th of the world's total population. Owing to differences in environment, race, living habits, and other factors, the structure of the intestinal flora of Chinese individuals is expected to have unique features; however, this has not been thoroughly examined. Here, we collected faecal samples from healthy adults living in three cities of China and investigated their gut microbiome using metagenomics and bioinformatics technology. We found that 11 core bacterial genera were present in all of the Chinese faecal samples; moreover, several patient characteristics (age, region, body mass index, physical exercise, smoking habits, and alcoholic drink, and yogurt consumption) were found to have different effects on the gut microbiome of healthy Chinese people. We also examined the distribution patterns of disease-related microorganisms (DRMs), revealing which DRMs can potentially be used as markers for assessment of health risk. We also developed a program called "Guthealthy" for evaluating the health status associated with the microbiome and DRM pattern in the faecal samples. The microbiota data obtained in this study will provide a basis for a healthy gut microbiome composition in the Chinese population.