While microbial‐based therapy has been considered as an effective strategy for treating diseases such as colon cancer, its safety remains the biggest challenge. Here, probiotics and prebiotics, which possess ideal biocompatibility and are extensively used as additives in food and pharmaceutical products, are combined to construct a safe microbiota‐modulating material. Through the host–guest chemistry between commercial Clostridium butyricum and chemically modified prebiotic dextran, prebiotics‐encapsulated probiotic spores (spores‐dex) are prepared. It is found that spores‐dex can specifically enrich in colon cancers after oral administration. In the lesion, dextran is fermented by C. butyricum, and thereby produces anti‐cancer short‐chain fatty acids (SCFAs). Additionally, spores‐dex regulate the gut microbiota, augment the abundance of SCFA‐producing bacteria (e.g., Eubacterium and Roseburia), and markedly increase the overall richness of microbiota. In subcutaneous and orthotopic tumor models, drug‐loaded spores‐dex inhibit tumor growth up to 89% and 65%, respectively. Importantly, no obvious adverse effect is found. The work sheds light on the possibility of using a highly safe strategy to regulate gut microbiota, and provides a promising avenue for treating various gastrointestinal diseases.
By leveraging the ability of Shewanella oneidensis MR-1 (S.oneidensis MR-1) to anaerobically catabolize lactate through the transfer of electrons to metal minerals for respiration, al actate-fueled biohybrid (Bac@MnO 2)w as constructed by modifying manganese dioxide (MnO 2)n anoflowers on the S. oneidensis MR-1 surface.T he biohybrid Bac@MnO 2 uses decorated MnO 2 nanoflowers as electron receptor and the tumor metabolite lactate as electron donor to make ac omplete bacterial respiration pathway at the tumor sites,which results in the continuous catabolism of intercellular lactate.A dditionally,d ecorated MnO 2 nanoflowers can also catalyze the conversion of endogenous hydrogen peroxide (H 2 O 2)into generate oxygen (O 2), which could prevent lactate production by downregulating hypoxia-inducible factor-1a (HIF-1a)e xpression. As lactate playsacritical role in tumor development, the biohybrid Bac@MnO 2 could significantly inhibit tumor progression by coupling bacteria respiration with tumor metabolism.
The excessive lactate in the tumor microenvironment always leads to poor therapeutic outcomes of chemotherapy. In this study, a self-driven bioreactor (defined as SO@MDH, where SO is Shewanella oneidensis MR-1 and MDH is MIL-101 metal–organic framework nanoparticles/doxorubicin/hyaluronic acid) is rationally constructed via the integration of doxorubicin (DOX)-loaded metal–organic framework (MOF) MIL-101 nanoparticles with SO to sensitize chemotherapy. Owing to the intrinsic tumor tropism and electron-driven respiration of SO, the biohybrid SO@MDH could actively target and colonize hypoxic and eutrophic tumor regions and anaerobically metabolize lactate accompanied by the transfer of electrons to Fe3+, which is the key component of the MIL-101 nanoparticles. As a result, the intratumoral lactate would undergo continuous catabolism coupled with the reduction of Fe3+ to Fe2+ and the subsequent degradation of MIL-101 frameworks, leading to an expeditious drug release for effective chemotherapy. Meanwhile, the generated Fe2+ will be promptly oxidized by the abundant hydrogen peroxide in the tumor microenvironment to reproduce Fe3+, which is, in turn, beneficial to circularly catabolize lactate and boost chemotherapy. More importantly, the consumption of intratumoral lactic acid could significantly inhibit the expression of multidrug resistance-related ABCB1 protein (also named P-glycoprotein (P-gp)) for conquering drug-resistant tumors. SO@MDH demonstrated here holds high tumor specificity and promising chemotherapeutic efficacy for suppressing tumor growth and overcoming multidrug resistance, confirming its potential prospects in cancer therapy.
As an emerging cancer treatment strategy, ferroptosis is greatly restricted by excessive glutathione (GSH) in tumor microenvironment (TME) and low reactive oxygen species (ROS) generation efficiency. Here, this work designs self‐assembled copper‐alanine nanoparticles (CACG) loaded with glucose oxidase (GOx) and cinnamaldehyde (Cin) for in situ glutathione activated and enzymatic cascade‐enhanced ferroptosis and immunotherapy. In response to GSH‐rich and acidic TME, CACG allows to effectively co‐deliver Cu2+, Cin, and GOx into tumors. Released Cin consumes GSH through Michael addition, accompanying with the reduction of Cu2+ into Cu+ for further GSH depletion. With the cascade of Cu+‐catalyzed Fenton reactions and enzyme‐catalyzed reactions by GOx, CACG could get rid of the restriction of insufficient hydrogen peroxide in TME, leading to a robust and constant generation of ROS. With the high efficiency of GSH depletion and ROS production, ferroptosis is significantly enhanced by CACG in vivo. Moreover, elevated oxidative stress triggers robust immune responses by promoting dendritic cells maturation and T cell infiltration. The in vivo results prove that CACG could efficiently inhibit tumor growth in 4T1 tumor‐bearing mouse model without causing obvious systemic toxicity, suggesting the great potential of CACG in enhancing ferroptosis and immunotherapy for effective cancer treatment.
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