Minimalist Nanocomplex with Dual Regulation of Endothelial Function and Inflammation for Targeted Therapy of Inflammatory Vascular Diseases.

Vascular disorders, characterized by vascular endothelial dysfunction combined with inflammation, are correlated with numerous fatal diseases, such as coronavirus disease-19 and atherosclerosis. Achieving vascular normalization is an urgent problem that must be solved when treating inflammatory vascular diseases. Inspired by the vascular regulatory versatility of nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) catalyzing l-arginine (l-Arg), the eNOS-activating effects of l-Arg, and the powerful anti-inflammatory and eNOS-replenishing effects of budesonide (BUD), we constructed a bi-prodrug minimalist nanoplatform co-loaded with BUD and l-Arg via polysialic acid (PSA) to form BUD-l-Arg@PSA. This promoted vascular normalization by simultaneously regulating vascular endothelial dysfunction and inflammation. Mediated by the special affinity between PSA and E-selectin, which is highly expressed on the surface of activated endothelial cells (ECs), BUD-l-Arg@PSA selectively accumulated in activated ECs, targeted eNOS expression and activation, and promoted NO production. Consequently, the binary synergistic regulation of the NO/eNOS signaling pathway occurred and improved vascular endothelial function. NO-induced nuclear factor-kappa B alpha inhibitor (IκBα) stabilization and BUD-induced nuclear factor-kappa B (NF-κB) response gene site occupancy achieved dual-site blockade of the NF-κB signaling pathway, thereby reducing the inflammatory response and inhibiting the infiltration of inflammation-related immune cells. In a renal ischemia-reperfusion injury mouse model, BUD-l-Arg@PSA reduced acute injury. In an atherosclerosis mouse model, BUD-l-Arg@PSA decreased atherosclerotic plaque burden and improved vasodilation. This represents a revolutionary therapeutic strategy for inflammatory vascular diseases.

Targeting Ibrutinib to Tumor-Infiltrating T Cells with a Sialic Acid Conjugate-Modified Phospholipid Complex for Improved Tumor Immunotherapy.

Immune checkpoint blockade (ICB) treatment for the clinical therapy of numerous malignancies has attracted widespread attention in recent years. Despite being a promising treatment option, developing complementary strategies to enhance the proportion of patients benefiting from ICB therapy remains a formidable challenge because of the complexity of the tumor microenvironment. Ibrutinib (IBR), a covalent inhibitor of Bruton's tyrosine kinase (BTK), has been approved as a clinical therapy for numerous B-cell malignancies. IBR also irreversibly inhibits interleukin-2 inducible T cell kinase (ITK), an essential enzyme in Th2-polarized T cells that participates in tumor immunosuppression. Ablation of ITK by IBR can elicit Th1-dominant antitumor immune responses and potentially enhance the efficacy of ICB therapy in solid tumors. However, its poor solubility and rapid clearance in vivo restrict T cell targetability and tumor accumulation by IBR. A sialic acid derivative-modified nanocomplex (SA-GA-OCT@PC) has been reported to improve the efficacy of IBR-mediated combination immunotherapy in solid tumors. In vitro and in vivo experiments showed that SA-GA-OCT@PC effectively accumulated in tumor-infiltrating T cells mediated by Siglec-E and induced Th1-dominant antitumor immune responses. SA-GA-OCT@PC-mediated combination therapy with PD-L1 blockade agents dramatically suppressed tumor growth and inhibited tumor relapse in B16F10 melanoma mouse models. Overall, the combination of the SA-modified nanocomplex platform and PD-L1 blockade offers a treatment opportunity for IBR in solid tumors, providing novel insights for tumor immunotherapy.

Polysialic Acid Self-assembled Nanocomplexes for Neutrophil-Based Immunotherapy to Suppress Lung Metastasis of Breast Cancer.

The role of neutrophils in tumor metastasis has recently attracted widespread interest. Neutrophils are the most abundant immune cells in human peripheral blood, and large numbers can spontaneously migrate to metastatic sites, where they form an immunosuppressive microenvironment. Polysialic acid (PSA) can target peripheral blood neutrophils (PBNs) mediated by L-selectin, and abemaciclib (ABE) and mitoxantrone (MIT) can treat immunosuppressive microenvironments. Here, we aimed to inhibit lung metastasis of breast cancer and improve chemoimmunotherapy by designing a PSA-modified ABE and MIT co-delivery system (AM-polyion complex (PIC)) to target PBNs in mice with metastatic tumors. We found that through electrostatic interactions between the strong negative charge of PSA and the positive charge of the drug can form stable nanocomplexes and that spontaneous migration of neutrophils can mediate the aggregation of these complexes in the lungs, induce antimetastatic immune responses, enhance the effectiveness of cytotoxic T lymphocytes (CTLs), and inhibit regulatory T cell (Treg) proliferation in vivo and in vitro. Pharmacodynamic results suggested that neutrophil-mediated AM-PIC chemoimmunotherapy inhibited tumor metastasis in mice with lung metastasis of 4T1 breast cancer. Overall, PSA-modified nanocomplexes offer promising neutrophil-mediated, targeted drug delivery systems to treat lung metastasis of breast cancer.

Sialic acid conjugate-modified liposomal platform modulates immunosuppressive tumor microenvironment in multiple ways for improved immune checkpoint blockade therapy.

Immune checkpoint blockade (ICB) treatment is promising for the clinical therapy of numerous malignancies. However, most cancer patients rarely benefit from such single-agent immunotherapies because of the complexity of both the tumor and tumor microenvironment. A tumor-specific liposomal vehicle (DOX-SAL) modified with a sialic acid-cholesterol conjugate (SA-CH) and remotely loaded with doxorubicin (DOX) is herein reported for improving chemoimmunotherapy. The intravenous administration of DOX-SAL dramatically downregulates tumor-associated macrophage (TAM)-mediated immunosuppression, inhibits immunoregulatory functions, and promotes intratumoral infiltration of CD8+ T cells. Compared to conventional liposomes, DOX-SAL-mediated combination therapy with a PD-1-blocking monoclonal antibody (aPD-1 mAb) almost completely eliminates B16F10 tumors and efficiently inhibits 4T1 tumors. Moreover, cancer stem cells exhibit efficient tumor-initiating, tumor-propagating, and immunosuppressive tumor microenvironment-shaping capabilities. To further improve the treatment efficacy of an immunologically "cold" tumor, metformin (MET), which selectively eradicates breast cancer tumor stem cells, is co-encapsulated with DOX into liposomes to develop DOX/MET-SAL. The combination therapy with DOX/MET-SAL and aPD-1 mAb in a 4T1 orthotopic mouse model indicates their synergetic benefit on primary tumor inhibition, metastasis suppression, and survival rate improvement. Thus, the multifunctional liposomal platform has potential value for ICB combination immunotherapy.