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.
Clinical treatment efficacy of oral bacterial therapy
has been
largely limited by insufficient gut retention of probiotics. Here,
we developed a bioorthogonal-mediated bacterial delivery strategy
for enhancing probiotics colonization by modulating bacterial adhesion
between probiotics and gut inhabitants. Metabolic amino acid engineering
was applied to metabolically incorporate azido-decorated d-alanine into peptidoglycans of gut inhabitants, which could enable in situ bioorthogonal conjugation with dibenzocyclooctyne
(DBCO)-modified probiotics. Both in vitro and in vivo studies demonstrated that the occurrence of the
bioorthogonal reaction between azido- and DBCO-modified bacteria could
result in obvious bacterial adhesion even in a complex physiological
environment. DBCO-modified Clostridium butyricum (C. butyricum) also showed more efficient reservation in
the gut and led to obvious disease relief in dextran sodium sulfate-induced
colitis mice. This strategy highlights metabolically modified gut
inhabitants as artificial reaction sites to bind with DBCO-decorated
probiotics via bioorthogonal reactions, which shows great potential
for enhancing bacterial colonization.
Local lung microbiota is closely associated with lung tumorigenesis and therapeutic response. It is found that lung commensal microbes induce chemoresistance in lung cancer by directly inactivating therapeutic drugs via biotransformation. Accordingly, an inhalable microbial capsular polysaccharide (CP)‐camouflaged gallium‐polyphenol metal–organic network (MON) is designed to eliminate lung microbiota and thereby abrogate microbe‐induced chemoresistance. As a substitute for iron uptake, Ga3+ released from MON acts as a “Trojan horse” to disrupt bacterial iron respiration, effectively inactivating multiple microbes. Moreover, CP cloaks endow MON with reduced immune clearance by masquerading as normal host‐tissue molecules, significantly increasing residence time in lung tissue for enhanced antimicrobial efficacy. In multiple lung cancer mice models, microbe‐induced drug degradation is remarkably inhibited when drugs are delivered by antimicrobial MON. Tumor growth is sufficiently suppressed and mouse survival is prolonged. The work develops a novel microbiota‐depleted nanostrategy to overcome chemoresistance in lung cancer by inhibiting local microbial inactivation of therapeutic drugs.
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