Janus Silica Nanoparticle-Based Tumor Microenvironment Modulator for Restoring Tumor Sensitivity to Programmed Cell Death Ligand 1 Immune Checkpoint Blockade Therapy

Abstract

An immunosuppressive tumor microenvironment (TME) with inadequate and exhausted tumor-infiltrating cytotoxic lymphocytes and abundant cellular immunosuppressors is the major obstacle responsible for the poor efficacy of PD-1/PD-L1 (programmed cell death 1 and its ligand 1) immune checkpoint blockade (ICB) therapy. Herein, a Janus silica nanoparticle (JSNP)-based immunomodulator is explored to reshape the TME for boosting the therapeutic outcomes of αPD-L1 therapy. The designed JSNP has two distinct domains, namely, an ultra pH-responsive side (UPS), which could encapsulate PI3Kγ inhibitor IPI549 in the pore structure, and a polycation-grafted intra-glutathione (GSH)-sensitive side (IGS), which could absorb CXCL9 cDNA on the surface. The final IPI549@UPS-IGS-PDMAEMA@CXCL9 cDNA (IUIPC) could release IPI549 in weak acid TME to target myeloid-derived suppressor cells (MDSCs) to reverse negative immunoregulation and then release CXCL9 cDNA in tumor cells with abundant GSH for sustained CXCL9 chemokine expression and secretion to improve cytotoxic lymphocyte recruitment signals, thereby jointly restoring tumor sensitivity to PD-1/PD-L1 ICB therapy. As expected, the IUIPC-mediated TME remodeling during αPD-L1 therapy significantly ameliorated TME immunosuppression, as well as induced potent systemic antitumor immune responses, which ultimately achieved a robustly boosted antitumor efficacy proven by remarkable suppression of primary tumor growth, obvious prevention of tumor recurrence, and significant regression of abscopal tumors. Hence, the IUIPC-mediated TME-regulating strategy provides an enormous perspective for the improvement of PD-1/PD-L1 ICB therapy.

Revolutionizing cancer immunotherapy: unleashing the potential of bispecific antibodies for targeted treatment

“…Obstructing inhibitory checkpoints can revive weary neoplasmpermeating T cells (114). Inhibitory receptors such as PD1, mucindomain containing3 (TIM3), and lymphocyteactivation gene 3 (LAG3) are abundantly expressed when T cells are in a worn-out condition, which results in defective effector outcomes (193)(194)(195). Immune checkpoint-targeting BsAbs are arising following the therapeutic efficacy of anti-CTLA4 (cytotoxic T lymphocyte antigen 4), anti-programmed cell death protein 1 Mechanism of action of BsAb: redirection of immune cells.…”

Efficient Fabrication of Janus Particles with Active Groups and Application in Emulsion Stabilization and Interfacial Catalysis

“…The Janus material has garnered significant attention. Due to its unique surface chemical composition and intricate geometric structure, it possesses diverse functionalities and exhibits remarkable adaptability in complex and dynamic application environments, rendering it extensively utilized in analytical chemistry, , medical immunology, , microelectronics technology, , and other related fields. − In the course of continuous exploration, researchers have developed various methods for the preparation of Janus particles. These methods include interface protection techniques, , emulsion polymerization approaches, , microfluidic strategies, , self-assembly methodologies, , phase separation methodologies, , and other avenues, , among which emulsion polymerization is one of the commonly used methods.…”

Injectable Zwitterionic Physical Hydrogel with Enhanced Chemodynamic Therapy and Tumor Microenvironment Remodeling Properties for Synergistic Anticancer Therapy

“…Surgical resection is the first-line clinical treatment for solid tumors including breast cancer, the most common malignant tumors for women. − However, surgery can only partially remove solid tumors, and residual microtumors will lead to recurrence and metastasis. − Up to one-third of patients develop tumor recurrence after surgery and have a high risk of mortality. , In addition, it has been reported that surgery itself may induce an immunosuppressive tumor microenvironment (TME), which not only promotes the invasion and proliferation of tumor cells but also inhibits the activity of antitumor immune cells, leading to tumor recurrence and metastasis. − Although postoperative systemic chemotherapy can partially prevent tumor recurrence, it cannot specifically target the tumor, which may lead to low drug concentration at the resection site and cause side effects. , Therefore, an effective strategy to overcome these limitations and prevent postoperative tumor recurrence is urgently required, achieving higher drug concentration at the tumor site, eliminating residual tumor cells locally and precisely, and regulating the immunosuppression of the TME after surgery to improve the effects of immunotherapy.…”