Microfluidics‐Enabled Nanovesicle Delivers CD47/PD‐L1 Antibodies to Enhance Antitumor Immunity and Reduce Immunotoxicity in Lung Adenocarcinoma

Abstract

The CD47/PD-L1 antibodies combination exhibits durable antitumor immunity but also elicits excessive immune-related adverse events (IRAEs) caused by the on-target off-tumor immunotoxicity, hindering their clinical benefits greatly. Here, a microfluidics-enabled nanovesicle using ultra-pH-sensitive polymer mannose-poly(carboxybetaine methacrylate)-poly(hydroxyethyl piperidine methacrylate) (Man-PCB-PHEP) is developed to deliver CD47/PD-L1 antibodies (NCPA) for tumor-acidity-activated immunotherapy. The NCPA can specifically release antibodies in acidic environment, thereby stimulating the phagocytosis of bone marrow-derived macrophages. In mice bearing Lewis lung carcinoma, NCPA shows significantly improved intratumoral CD47/PD-L1 antibodies accumulation, promoted tumor-associated macrophages remodeling to antitumoral status, and increased infiltration of dendritic cells and cytotoxic T lymphocytes, resulting in more favorable treatment effect compared to those of free antibodies. Additionally, NCPA also shows less IRAEs, including anemia, pneumonia, hepatitis, and small intestinal inflammation in vivo. Altogether, a potent dual checkpoint blockade immunotherapy utilizing NCPA with enhanced antitumor immunity and reduced IRAEs is demonstrated.

Advancing the Boundaries of Immunotherapy in Lung Adenocarcinoma with Idiopathic Pulmonary Fibrosis by a Biomimetic Proteinoid Enabling Selective Endocytosis

“…The systemic introduction of anti-PD-1 mAb would promote lymphocyte infiltration into the lungs by inducing an unexpected activation of the immune response, consequently triggering cytokine release syndrome and ultimately resulting in CIP. 38 Subsequently, we delved into the potential mechanisms that could account for the disparity in CIP occurrence between EMS-PDBP and anti-PD-1 mAb in the LC-PF model through RNA- seq analysis. In this context, mice were subjected to intravenous doses of anti-PD-1 mAb (3 mg/kg, every other day) and EMS-PDBP (2 mg/kg, once daily) for 5 cycles.…”

Recent advances in biomaterial designs for assisting CAR-T cell therapy towards potential solid tumor treatment

“…117 Su et al created a microfluidic nanovesicle for the delivery of CD47/PD-L1 antibodies that promoted TAM polarization toward M1 and immune cell infiltration with better therapeutic effects than free antibodies, offering a new idea for improving immunotherapy with immune checkpoint inhibitors. 118 Hu et al loaded CAR-T cell targeting CSPG4 antigens, anti-PD-L1 blocking antibody-conjugated human platelets (P-aPDL1) and cytokine IL-15 into a hydrogel using a methacrylate-hyaluronic acid (HAMA) hydrogel as a vehicle to release CAR-T cells and platelets conjugated with checkpoint inhibitors, which could inhibit local tumor recurrence in mice and the growth of distant tumors. 56 One of the main reasons for ineffective or weak efficacy of CAR-T cell therapy is insufficient T cell expansion and poor T cell persistence.…”

The interplay between the tumor microenvironment and tumor-derived small extracellular vesicles in cancer development and therapeutic response

“… 152 Additionally, Su et al introduced a novel therapeutic approach involving the dual immune checkpoint blockade of CD47/PD-L1, specifically targeting the acidic microenvironment of tumors. 153 This intervention effectively activates CD47/PD-L1, leading to a significant enhancement of the efficacy of CD47/PD-L1 antibody treatment for lung cancer. 153 Despite being limited to preclinical stages at present, the application of pH-selective antibodies shows significant promise in improving the TME and addressing the challenges associated with the efficacy and safety of antibody therapy as a standalone treatment.…”