Immunotherapy
has provided a promising strategy for the treatment
of cancers. However, even in tumors with high antigen burdens, the
systemic inhibition of the antigen presentation still greatly restricts
the application of immunotherapy. Here, we construct a tumor protein-engineering
system based on the functional tripeptide, Asp-Phe-Tyr (DFY), which
can automatically collect and deliver immunogenetic tumor proteins
from targeted cells to immune cells. Through a tyrosinase-catalyzed
polymerization, the DFY tripeptide selectively accumulates in tyrosinase
high-expressed melanoma cells. Then quinone-rich intermediates are
covalently linked with tumor-specific proteins by Michael addition
and form tumor protein-carried microfibers that could be engulfed
by antigen-presenting cells and exhibited tumor antigenic properties
for boosting immune effect. In melanoma cells with deficient antigen
presentation, this system can successfully enrich and transport tumor
antigen-containing proteins to immune cells. Furthermore, in the in vivo study on murine melanoma, the transdermal delivery
of the DFY tripeptide suppressed the tumor growth and the postsurgery
recurrence. Our findings provide an avenue for the regulation of the
immune system on an organism by taking advantage of certain polymerization
reactions by virtue of chemical biology.
The differential tumor environment guides various antitumor
drug
delivery strategies for efficient cancer treatment. Here, based on
the special bacteria-enriched tumor environment, we report a different
drug delivery strategy by targeting bacteria inhabiting
tumor sites. With a tissue microarray analysis, it was found that
bacteria amounts displayed significant differences between tumor and
normal tissues. Bacteria-targeted mesoporous silica nanoparticles
decorated with bacterial lipoteichoic acid (LTA) antibody (LTA-MSNs)
could precisely target bacteria in tumors and deliver antitumor drugs.
By the intravenous administration of bacteria-targeted nanoparticles,
we showed in mice with colon cancer, lung cancer, and breast cancer
that LTA-MSNs exhibited a high tumor-targeting ability. As a proof-of-concept
study, tumor microbes as some of the characteristics of a tumor environment
could be utilized as potential targets for tumor targeting. This bacteria-guided
tumor-targeting strategy might have great potential in differential
drug delivery and cancer treatment.
Despite the recognition that the gut microbiota acts a clinically significant role in cancer chemotherapy, both mechanistic understanding and translational research are still limited. Maximizing drug efficacy requires an in-depth understanding of how the microbiota contributes to therapeutic responses, while microbiota modulation is hindered by the complexity of the human body. To address this issue, a 3D experimental model named engineered microbiota (EM) is reported for bridging microbiota-drug interaction research and therapeutic decision-making. EM can be manipulated in vitro and faithfully recapitulate the human gut microbiota at the genus/species level while allowing co-culture with cells, organoids, and isolated tissues for testing drug responses. Examination of various clinical and experimental drugs by EM reveales that the gut microbiota affects drug efficacy through three pathways: immunological effects, bioaccumulation, and drug metabolism. Guided by discovered mechanisms, custom-tailored strategies are adopted to maximize the therapeutic efficacy of drugs on orthotopic tumor models with patient-derived gut microbiota. These strategies include immune synergy, nanoparticle encapsulation, and host-guest complex formation, respectively. Given the important role of the gut microbiota in influencing drug efficacy, EM will likely become an indispensable tool to guide drug translation and clinical decision-making.
Taking inspiration from percutaneous ethanol injection (PEI) for tumor ablation, an acetaldehyde generator (SC@ZIF@ADH) is constructed for tumor treatment by modifying a metal–organic framework nanocarrier (ZIF), which is loaded with alcohol dehydrogenase (ADH), onto the surface of Saccharomyces cerevisiae (SC). Oral administration of SC@ZIF@ADH can target tumor via mannose‐mediated targeting to tumor associated macrophages (TAMs) and generate ethanol at the hypoxic tumor areas. Ethanol is subsequently catalyzed to toxic acetaldehyde by ADH, inducing tumor cells apoptosis and polarizing TAMs toward the anti‐tumor phenotype. In vivo animal results show that this acetaldehyde generator can cause a temulence‐like reaction in the tumor, significantly inhibiting tumor progression, and might provide an intelligent and nonsurgical substitute for PEI therapy.
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