Engineering Crystallinity Gradients for Tailored CaO2 Nanostructures: Enabling Alkalinity-Reinforced Anticancer Activity with Minimized Ca2+/H2O2 Production.

CaO2 nanoparticles (CNPs) can produce toxic Ca2+ and H2O2 under acidic pH, which accounts for their intrinsic anticancer activity but at the same time raises safety concerns upon systemic exposure. Simultaneously realizing minimized Ca2+/H2O2 production and enhanced anticancer activity poses a dilemma. Herein, we introduce a "crystallinity gradient-based selective etching" (CGSE) strategy, which is realized by creating a crystallinity gradient in a CNP formed by self-assembled nanocrystals. The nanocrystals distributed in the outer layer have a higher crystallinity and thus are chemically more robust than those distributed in the inner layer, which can be selectively etched. CGSE not only leads to CNPs with tailored single- and double-shell hollow structures and metal-doped compositions but more surprisingly enables significantly enhanced anticancer activity as well as tumor growth inhibition under limited Ca2+/H2O2 production, which is attributed to an alkalinity-reinforced lysosome-dependent cell death pathway.

A Sub-6 nm MnFe2O4-dichloroacetic acid nanocomposite modulates tumor metabolism and catabolism for reversing tumor immunosuppressive microenvironment and boosting immunotherapy.

Adenosine and lactate accumulated in tumor microenvironment are two major causes of immunosuppression, their concurrent downregulation holds promise in effective cancer immunotherapy, but remains challenging. Here, a sub-6 nm MnFe2O4 conjugated with dichloroacetic acid (DCA) nanoparticle is developed to modulate tumor glucose metabolism and ATP catabolism for reversing the tumor immunosuppressive microenvironment. The ultrasmall MnFe2O4-DCA nanoparticle can efficiently enter mitochondria and supply oxygen, improving the bioactivity of DCA to regulate glucose metabolism and reduce lactate production ca. 100 times higher than free DCA itself. Moreover, this design significantly downregulates CD39 and CD73 expression than DCA or MnFe2O4 alone, which consequently decreases the extracellular ATP catabolism. The concurrent regulation of glucose metabolism and ATP catabolism leads to increased immunostimulatory ATP level and decreased immunosuppressive adenosine and lactate levels in tumor microenvironment, eventually amplified dendritic cells maturation, enhanced cytotoxic T lymphocyte response, and improved cancer immunotherapy efficacy.

Immune-regulating bimetallic metal-organic framework nanoparticles designed for cancer immunotherapy.

Immunogenic cell death (ICD) is a promising strategy in cancer immunotherapy to induce high immunogenicity and activate the immune system. However, its efficacy is counteracted by the concurrent exposure of phosphatidylserine (PS), an immunosuppressive signal on the surface of cancer cells. Here we report the synthesis of a bimetallic metal-organic framework (MOF) nanoparticle containing Gd3+ and Zn2+ (Gd-MOF-5) that can be used as an immunomodulator to downregulate the immunosuppressive PS signal and an ICD inducer to upregulate immunostimulatory signals. Gd3+ inhibits PS externalization via inhibiting the activity of scramblase, an enzyme to transfer PS to the outer leaflet of plasma membrane. Moreover, intracellular Zn2+ overload activates endoplasmic reticulum stress for ICD induction. In combination with an immune checkpoint inhibitor (PD-L1 antibody, denoted as aPDL1), Gd-MOF-5 activated potent immune response and effectively inhibited primary and distal tumor growth in a bilateral 4T1 tumor model. This work presents a new strategy using designed MOF materials to modulate the cell signalling and immunosuppressive microenvironment to improve the outcome of cancer immunotherapy.

Eliciting Immunogenic Cell Death via a Unitized Nanoinducer.

Utilizing chemotherapeutics to induce immunogenic cell death (ICD) is a promising strategy to sensitize tumor cells and induce anticancer immunity. However, the application of traditional ICD inducers, such as chemodrugs, is largely hindered by their low tumor selectivity and severe side effects. Here, a new unitized ICD nanoinducer with high potency and cancer cell specificity is reported to achieve effective cancer immunotherapy. This nanoinducer is composed of disulfide-bond-incorporated organosilica nanoparticles, curcumin (CUR), and iron oxide nanoparticles, which can deplete intracellular glutathione, produce hydroxyl radicals, and induce cancer-cell-specific Ca2+ depletion as well as thioredoxin reductase inhibition. While the components are unable to induce ICD individually, their complementary pharmaceutical activities significantly elevate intracellular oxidative stress and endoplasmic reticulum stress in parallel. Consequently, ICD and systemic antitumor immunity can be elicited. Compared to the conventional ICD inducer doxorubicin, the unitized nanoinducer exhibits significantly improved ICD-inducing activity and cancer cell selectivity.

Modification with Metallic Bismuth as Efficient Strategy for the Promotion of Photocatalysis: The Case of Bismuth Phosphate.

A BiPO4 nanostructure modified with Bi nanoparticles rich in oxygen vacancies in the surface and subsurface was prepared through a one-pot solvothermal treatment utilizing the weak reductive ability of ethylene glycol (EG). The presence of Bi nanocrystals and oxygen vacancies is beneficial for the separation and consumption of photogenerated electrons and holes where Bi nanocrystals act as active sites for the formation of (.) OH and oxygen vacancies are active sites for (.) O2 (-) formation. The enhanced photocatalytic activity is ascribed to the synergistic effect of Bi nanocrystals and surface oxygen vacancies.

Time-dependent evolution of the Bi(3.64)Mo(0.36)O(6.55)/Bi2MoO6 heterostructure for enhanced photocatalytic activity via the interfacial hole migration.

Hierarchical Bi(3.64)Mo(0.36)O(6.55)/Bi2MoO6 isotype heterostructures were successfully prepared via a one-pot hydrothermal route by using Bi2O3 porous nanospheres as a sacrificial template. By tuning the reaction time, the formation process of the Bi(3.64)Mo(0.36)O(6.55)/Bi2MoO6 heterostructure involving Mo etching, phase transition and anisotropic growth was clearly identified. More importantly, the Bi(3.64)Mo(0.36)O(6.55)/Bi2MoO6 heterostructure displayed remarkably enhanced photocatalytic activity for dye photodegradation than pure phase bismuth molybdate due to the efficient electron-hole separation and the interfacial photogenerated hole migration from inside the Bi(3.64)Mo(0.36)O(6.55) layer to outside the Bi2MoO6 layer. The opposite hole migration from the outer layer to the inner layer was also detected in Bi2O3/Bi2WO6 heterostructures, which resulted in the decrease of photocatalytic activity, further verifying the importance of hole migration direction. This work provides a novel route to fabricate heterostructured photocatalysts, as well as gives a strategy for mediating the charge migration to improve photocatalytic performance.