Reprogramming Immunodeficiency in Lung Metastases via PD-L1 siRNA Delivery and Antigen Capture of Nanosponge-Mediated...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Immunotherapy

Background:

• Hypovascular lung metastases are immune-privileged, hindering T cell infiltration and immunotherapy effectiveness.
• Dendritic cells (DCs) are crucial for initiating antitumor immune responses but face challenges in metastatic environments.

Purpose of the Study:

• To develop a pH-responsive catalyst for targeted delivery of PD-L1 siRNA to lung metastases.
• To enhance antigen presentation and T cell infiltration for improved immunotherapy outcomes.

Main Methods:

• A novel catalyst, TP-SL@PB, was synthesized using tumor penetration polymer (TP), solid lipids (SL), and Prussian blue (PB).
• The catalyst utilizes organ-selective targeting and charge conversion for accumulation in lung metastases.
• It facilitates siRNA delivery, PD-L1 downregulation, and self-cascade antigen capture via catalytic and antigen-sponge effects.

Main Results:

• TP-SL@PB effectively accumulated in hypovascular lung metastases.
• The catalyst enhanced siRNA delivery, leading to PD-L1 downregulation and tumor-associated antigen release.
• TP-SL@PB acted as a catalytic nanosponge, promoting DC maturation and T cell infiltration for sustained immune activation.

Conclusions:

• TP-SL@PB demonstrates potential as a lung metastasis-penetrating catalytic nanosponge for immunotherapy.
• This approach reprograms immunodeficiency by enhancing T cell infiltration and antitumor responses.
• The strategy offers a promising method to overcome barriers in treating intractable metastatic tumors.