Gene augmented nuclear-targeting sonodynamic therapy via Nrf2 pathway-based redox balance adjustment boosts peptide-based anti-PD-L1 therapy on colorectal cancer.

BACKGROUND: Colorectal cancer is known to be resistant to immune checkpoint blockade (ICB) therapy. Sonodynamic therapy (SDT) has been reported to improve the efficacy of immunotherapy by inducing immunogenic cell death (ICD) of cancer. However, the SDT efficacy is extremely limited by Nrf2-based natural redox balance regulation pathway in cancer cells in response to the increased contents of reactive oxygen species (ROS). Nuclear-targeting strategy has shown unique advantages in tumor therapy by directly destroying the DNA. Thus it can be seen that Nrf2-siRNA augmented nuclear-targeting SDT could boost ICB therapy against colorectal cancer. RESULTS: The nuclear-targeting delivery system TIR@siRNA (TIR was the abbreviation of assembled TAT-IR780) with great gene carrier capacity and smaller diameter (< 60 nm) was designed to achieve the gene augmented nuclear-targeting SDT facilitating the anti-PD-L1 (programmed cell death-ligand-1) therapy against colorectal cancer. In CT26 cells, TIR@siRNA successfully delivered IR780 (the fluorescent dye used as sonosensitizer) into cell nucleus and Nrf2-siRNA into cytoplasm. Under US (utrasound) irradiation, TIR@siRNA notably increased the cytotoxicity and apoptosis-inducing activity of SDT through down-regulating the Nrf2, directly damaging the DNA, activating mitochondrial apoptotic pathway while remarkably inducing ICD of CT26 cells. In CT26 tumor-bearing mice, TIR@siRNA mediated gene enhanced nuclear-targeting SDT greatly inhibited tumor growth, noticeably increased the T cell infiltration and boosted DPPA-1 peptide-based anti-PD-L1 therapy to ablate the primary CT26 tumors and suppress the intestinal metastases. CONCLUSIONS: All results demonstrate that TIR@siRNA under US irradiation can efficiently inhibit the tumor progression toward colorectal CT26 cancer in vitro and in vivo by its mediated gene augmented nuclear-targeting sonodynamic therapy. Through fully relieving the immunosuppressive microenvironment of colorectal cancer by this treatment, this nanoplatform provides a new synergistic strategy for enhancing the anti-PD-L1 therapy to ablate colorectal cancer and inhibit its metastasis.

Platelet membrane-based biochemotactic-targeting nanoplatform combining PDT with EGFR inhibition therapy for the treatment of breast cancer.

Presently, the commonly used anti-tumor drugs lack targeting ability, resulting in a limited therapeutic efficacy and significant side effects. In this view, platelet membranes (PMs) not only exhibit specific binding of its P-selectin protein with CD44, which is highly expressed on breast cancer cells, to promote tumor-active targeting by PM biomimetic nanoplatforms, but also respond to vascular damage, thus inducing biochemotactic targeting to further facilitate the aggregation of these nanoplatforms. Therefore, in this study, a PM was applied to construct a biochemotactic-targeting nanotherapeutic platform based on dendritic large pore mesoporous silica nanoparticles (DLMSNs) co-loaded with chlorin e6 (Ce6) and lapatinib (LAP) to achieve the combination of photodynamic therapy (PDT) and EGFR inhibition therapy for breast cancer. Under laser irradiation, PM@DLMSN/Ce6/Lap could not only effectively kill breast tumor cells by the PDT, but also damage blood vessels. By combining the EGFR inhibition of LAP, PM@DLMSN/Ce6/Lap could better inhibit the migration and movement of tumor cells. In vitro and in vivo results showed that PM@DLMSN/Ce6/Lap could achieve active-targeting drug delivery to breast tumors and further recruit more nanoparticles to accumulate at tumor sites after the PDT-induced damage of blood vessels through biochemotactic targeting, achieving continuous EGFR inhibition to prevent tumor proliferation and metastasis. In conclusion, this study not only provides a new strategy for the clinical treatment of breast cancer, but also provides a design idea for improving the targeted delivery of anti-tumor drugs.

Endoplasmic reticulum-targeted NIR-II phototherapy combined with inflammatory vascular suppression elicits a synergistic effect against TNBC.

Recurrence and metastasis are the main reasons for failure in the treatment of triple-negative breast cancer (TNBC). Phototherapy, one of the most well-known potent cancer treatment models is highlighted by ablating primitive tumors with immunogenic cell death (ICD) and is associated with endoplasmic reticulum (ER) stress to elicit long-lasting anti-tumor immunity. However, the provoked inflammatory response after phototherapy will stimulate angiogenesis, which provides nutrition for tumor recurrence. Here, an ER-targeted nanoplatform was constructed based on hollow mesoporous Cu2-XS (HMCu2-XS) nanoparticles to suppress recurrence and metastasis of TNBC by combining photo-ablation and microenvironment remodeling. Profiting from the metal ion coordination and large hollow space, HMCu2-XS can be easily modified with p-toluenesulfonamide for ER-targeting and quantitatively loaded celecoxib (CXB) as a vascular inhibitor, thus obtaining ER-HMCu2-XS/CXB. ER-HMCu2-XS showed great photothermal and photodynamic efficiency for ablating 4T1 tumors and inducing ICD under NIR-II laser irradiation. Compared with non-ER-targeted nanosystems, the ER-targeted nanosystem elicited stronger ICDs and recruited more immune cells. Moreover, the thermal-responsively released CXB successfully inhibited angiogenesis after photothermal therapy. The data showed that the ER-HMCu2-XS/CXB mediated the triplicate therapeutic effect of photo-ablation, immune response activation, and vascular suppression effectively, preventing the recurrence and metastasis of TNBC. In conclusion, this work provides a synergistic strategy to enhance therapeutic outcomes in TNBC.

Stable colonization of Akkermansia muciniphila educates host intestinal microecology and immunity to battle against inflammatory intestinal diseases.

Gut microbial preparations are widely used in treating intestinal diseases but show mixed success. In this study, we found that the therapeutic efficacy of A. muciniphila for dextran sodium sulfate (DSS)-induced colitis as well as intestinal radiation toxicity was ~50%, and mice experiencing a positive prognosis harbored a high frequency of A. muciniphila in the gastrointestinal (GI) tract. Stable GI colonization of A. muciniphila elicited more profound shifts in the gut microbial community structure of hosts. Coexisting with A. muciniphila facilitated proliferation and reprogrammed the gene expression profile of Lactobacillus murinus, a classic probiotic that overtly responded to A. muciniphila addition in a time-dependent manner. Then, a magnetic-drove, mannose-loaded nanophase material was designed and linked to the surface of A. muciniphila. The modified A. muciniphila exhibited enhancements in inflammation targeting and intestinal colonization under an external magnetic field, elevating the positive-response rate and therapeutic efficacy against intestinal diseases. However, the unlinked cocktail containing A. muciniphila and the delivery system only induced negligible improvement of therapeutic efficacy. Importantly, heat-inactivated A. muciniphila lost therapeutic effects on DSS-induced colitis and was even retained in the GI tract for a long time. Further investigations revealed that the modified A. muciniphila was able to drive M2 macrophage polarization by upregulating the protein level of IL-4 at inflammatory loci. Together, our findings demonstrate that stable colonization of live A. muciniphila at lesion sites is essential for its anti-inflammatory function.