Xiupeng Wang

Despite recent clinical successes in cancer immunotherapy, it remains difficult to initiate a long-term anti-tumor effect. Therefore, repeated administrations of immune-activating agents are generally required in most cases. Herein, we propose an adjuvant particle size tuning strategy to initiate a long-term anti-tumor effect by one-shot vaccination. This strategy is based on the size-dependent immunostimulation mechanism of mesoporous silica particles. Hollow mesoporous silica (HMS) nanoparticles enhance the antigen uptake with dendritic cells around the immunization site in vivo. In contrast, hierarchically porous silica (HPS) microparticles prolong cancer antigen retention and release in vivo. The size tuning of the mesoporous silica adjuvant prepared by combining both nanoparticles and microparticles demonstrates the immunological properties of both components and has a long-term anti-tumor effect after one-shot vaccination. One-shot vaccination with HMS-HPS-ovalbumin (OVA)-Poly IC (PIC, a TLR3 agonist) increases CD4⁺ T cell, CD8⁺ T cell, and CD86⁺ cell populations in draining lymph nodes even 4 months after vaccination, as well as effector memory CD8⁺ T cell and tumor-specific tetramer⁺CD8⁺ T cell populations in splenocytes. The increases in the numbers of effector memory CD8⁺ T cells and tumor-specific tetramer⁺CD8⁺ T cells indicate that the one-shot vaccination with HMS-HPS-OVA-PIC achieved the longest survival time after a challenge with E.G7-OVA cells among all groups. The size tuning of the mesoporous silica adjuvant shows promise for one-shot vaccination that mimics multiple clinical vaccinations in future cancer immunoadjuvant development. This study may have important implications in the long-term vaccine design of one-shot vaccinations.

Improving the delivery of biomolecules to DCs and lymph nodes is critical to increasing their anti-tumor efficacy, reducing their off-target side effects, and improving their safety. In this study, Gd₂O₃ nanotubes with lengths of 70–80 nm, diameters of 20–30 nm, and pore sizes of up to 18 nm were synthesized using a facile one-pot solvothermal method. The Gd₂O₃ nanotubes showed good adsorption capacity of OVA and TLR7a, with a loading efficiency of about 100%. The Gd₂O₃ nanotubes showed pH-sensitive degradation and biomolecule release properties; the release of gadolinium ions, OVA, and TLR7a was slow at pH 7.4 and fast at pH 5. The Gd₂O₃ nanotubes showed 2.6–6.0 times higher payload retention around the injection site, 3.1 times higher cellular uptake, 1.7 times higher IL1β secretion, 1.4 times higher TNFα secretion by BMDCs, and markedly enhanced draining lymph node delivery properties. The combination of OVA, TLR7a, and Gd₂O₃ nanotubes significantly inhibited tumor growth and increased survival rate compared with only OVA-TLR7a, only OVA, and saline. The Gd₂O₃ nanotubes are biocompatible and can also be used as radiation sensitizers.

Clinically, cancer chemotherapy still faces unsatisfactory efficacy due to drug resistance and severe side effects, including tiredness, hair loss, feeling sick, etc. The clinical benefits of checkpoint inhibitors have revived hope for cancer immunotherapy, but the objective response rate of immune checkpoint inhibitors remains around 10–40%. Herein, two types of copper-doped mesoporous silica nanoparticles (MS-Cu–1 with a diameter of about 30 nm and MS-Cu–2 with a diameter of about 200 nm) were synthesized using a one-pot method. Both MS-Cu–1 and MS-Cu–2 nanoparticles showed excellent tumor microenvironment regulation properties with elevated extracellular and intracellular ROS generation, extracellular and intracellular oxygenation, and intracellular GSH depletion. In particular, MS-Cu–2 nanoparticles demonstrated a better microenvironment modulation effect than MS-Cu–1 nanoparticles. The DSF/MS-Cu composites with disulfiram (DSF) and copper co-delivery characteristics were prepared by a straightforward method using chloroform as the solvent. Cell survival rate and live/dead staining results showed that DSF and MS-Cu alone were not toxic to LLC cells, while a low dose of DSF/MS-Cu (1–10 μg/mL) showed a strong cell-killing effect. In addition, MS-Cu–2 nanoparticles released more Cu²⁺ in a weakly acidic environment (pH = 5) than in a physiological environment (pH = 7.4), and the Cu²⁺ released was 41.72 ± 0.96 mg/L in 1 h under weakly acidic conditions. UV–visible absorption spectrometry confirmed the production of tumor-killing drugs (CuETs). The intratumoral injection of DSF/MS-Cu significantly inhibited tumor growth in vivo by converting nontoxic DSF/MS-Cu into toxic CuETs. The combination of DSF/MS-Cu and anti-CTLA–4 antibody further inhibited tumor growth, showing the synergistic effect of DSF/MS-Cu and immune checkpoint inhibitors.

Current chemotherapy still suffers from unsatisfactory therapeutic efficacy, multi-drug resistance, and severe adverse effects, thus necessitating the development of techniques to confine chemotherapy drugs in the tumor microenvironment. Herein, we fabricated nanospheres of mesoporous silica (MS) doped with Cu (MS-Cu) and polyethylene glycol (PEG)-coated MS-Cu (PEG-MS-Cu) as exogenous copper supply systems to tumors. The synthesized MS-Cu nanospheres showed diameters of 30–150 nm with Cu/Si molar ratios of 0.041–0.069. Only disulfiram (DSF) and only MS-Cu nanospheres showed little cytotoxicity in vitro, whereas the combination of DSF and MS-Cu nanospheres showed significant cytotoxicity against MOC1 and MOC2 cells at concentrations of 0.2–1 μg/mL. Oral DSF administration in combination with MS-Cu nanospheres intratumoral or PEG-MS-Cu nanospheres intravenous administration showed significant antitumor efficacy against MOC2 cells in vivo. In contrast to traditional drug delivery systems, we herein propose a system for the in situ synthesis of chemotherapy drugs by converting nontoxic substances into antitumor chemotherapy drugs in a specific tumor microenvironment.

Combining MM NPs with DOX and the anti-CTLA-4 antibody simultaneously inhibited the growth of primary tumors and distant untreated tumors owing to the optimized TME regulatory functions from different aspects.