In situ tuning proangiogenic factor-mediated immunotolerance synergizes the tumoricidal immunity via a hypoxia-triggerable liposomal bio-nanoreactor

Abstract

Rationale: Vascular abnormality stemming from the hypoxia-driven elevation of proangiogenic factors is a hallmark for many solid malignant tumors, including colorectal cancer (CRC) and its liver metastasis. We report a hypoxia-triggered liposome-supported metal-polyphenol-gene bio-nanoreactor to tune the proangiogenic factor-mediated immunotolerance and synergize the elicited tumoricidal immunity for CRC treatment. Methods: With the aid of polyphenol gallic acid, Cu 2+ ion-based intracellular bio-nanoreactor was synthesized for the delivery of small interfering RNA targeting vascular endothelial growth factor and then cloaked with a hybrid liposomal membrane that harbored a hypoxia-responsive azobenzene derivative. In hypoxic tumor, the liposomal shell disintegrated, and a shrunk-size bio-nanoreactor was burst released. Intracellularly, Cu 2+ from the bio-nanoreactor catalyzed a Fenton-like reaction with glutathione, which efficiently converted H 2 O 2 to •OH and enabled a chemodynamic therapy (CDT) in tumor sites. With the alleviation of proangiogenic factor-mediated immunotolerance and high production of CDT-induced tumor-associated antigens, robust tumoricidal immunity was co-stimulated. Results: With colorectal tumor and its liver metastasis models, we determined the underlying mechanism of proangiogenic factor-mediated immunotolerance and highlighted that the liposomal bio-nanoreactor could create positive feedback among the critical players in the vascular endothelium and synergize the elicited tumoricidal immunity. Conclusion: Our work provides an alternative strategy for exerting efficient tumoricidal immunity in the proangiogenic factor-upregulated subpopulation of CRC patients and may have a wide-ranging impact on cancer immune-anti-angiogenic complementary therapy in clinics.

In Situ Biosynthesis of Reduced Alpha Hematite (α-Fe2O3) Nanoparticles by Stevia Rebaudiana L. Leaf Extract: Insights into Antioxidant, Antimicrobial, and Anticancer Properties

“…They have variable molecular weights, with a huge number of subgroups distinguished as flavonoids, chalcones, coumarins, hydroxycinnamic acids, hydroxybenzoic acids, etc. All these families are renowned as having antioxidant and antitumor properties [ 5 , 6 ]. However, hydroxycinnamic acids represent an important group of phenolic compounds derived from cinnamic acid through the phenylpropanoid pathway.…”

A Duplex CRISPR-Cas9 Ribonucleoprotein Nanomedicine for Colorectal Cancer Gene Therapy

“…Next, we evaluated whether the disruption of both mutant KRAS and APC could synergistically inhibit the tumor growth in an orthotopic CRC model. An orthotopic CRC model was established by injecting human SW480 colon cancer cells stably expressing luciferase into the cecum wall of BALB/c mice (Figure a). , As shown in Figure b, the systemic administration of duplex HAPD/RNP significantly extended the survival time to 50 days, whereas single editing of either APC or KRAS by HAPD/RNP only showed the moderate inhibitory effect. T7E1 assay results also suggested significant genome disruption in the mutant KRAS (15.4%) and APC (10.9%) loci in the tumor tissue (Figure c), which was further confirmed by Sanger sequencing (Figure d) and deep sequencing (Figure e).…”

“…In Vivo Synergistic Antitumor Efficacy on CRC Liver Metastasis Model. As the liver is the most common metastatic site for advanced CRC, 39,40 we established a CRC liver metastasis model by hemisplenic injection of SW480 cells into the liver (Figure 4a). As shown in Figure 4b, the systemic administration of duplex HAPD/RNP complexes effectively contributed to extending the survival time of the mouse model with CRC liver metastasis.…”

Metal Ion-Directed Functional Metal–Phenolic Materials

“…Textiles decorated with MPN@Ag NPs exhibited antibacterial activity against Gram-negative bacteria and outperformed a commercial bandage . Transition metal ions coordinated with phenolics have demonstrated their potential as antibacterial coatings for medical devices or implants (Figure b); among the transition metal ions studied, Cu 2+ ions have been the most extensively studied. − In a representative study, Huang and co-workers harnessed the antibacterial and antithrombotic properties of Cu 2+ to fabricate metal–phenolic–amine network-based coatings . The Cu 2+ -chelating coatings endowed the polyvinyl chloride tubes with durable and excellent antibacterial performance as well as the capability to produce the antithrombotic mediator nitric oxide gas in the presence of endogenous S -nitrosothiols from blood .…”