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

Abstract

The coexistence of lung adenocarcinoma (LUAD) with idiopathic pulmonary fibrosis (IPF), which has been extensively documented as a prominent risk factor for checkpoint inhibitor-related pneumonitis (CIP) in patients undergoing immunotherapy, has long been considered a restricted domain for the use of immune checkpoint inhibitors (ICIs). To overcome it, an approach was employed herein to specifically target PD-L1 within the cellular interior, surpassing the conventional focus solely on the cytomembrane, thereby facilitating the development of ICIs capable of distinguishing between LUAD cells and noncancerous cells based on their distinctive endocytic propensities. By exploiting the aurophilicity-driven self-assembly of a PD-L1 binding peptide (PDBP) and subsequently encapsulating it within erythrocyte membranes (EM), the resulting biomimetic ICIs protein EMS-PDBP exhibited extraordinary selectivity in internalizing LUAD cells, effectively targeting PD-L1 within cancer cells while hindering its membrane translocation. The EMS-PDBP treatment not only reactivated the antitumor immune response in the LUAD orthotopic allograft mouse model but also demonstrated a favorable safety profile by effectively eliminating any immunerelated adverse events (irAEs). Most significantly, EMS-PDBP successfully and safely restored the antitumor immune response in a mouse model of LUAD with coexistent IPF, thus shattering the confines of ICIs immunotherapy. The reported EMS-PDBP collectively offers a potential strategy for immune reactivation to overcome the limitations of immunotherapy in LUAD coexisting with IPF.

Editorial: Overcoming obstacles of cancer immunotherapy: the important role of emerging nanomedicine

“…They concluded CM-NPs hold great potential as a pivotal drug delivery strategy in the diagnosis and treatment of various malignancies, including breast cancer. Recent studies have revealed that biomimetic nanoparticles derived from erythrocyte membranes exhibit excellent tumor-targeting capabilities by altering the endocytosis mechanism (6,21). A recent study has introduced an innovative approach by developing an erythrocyte membrane biomimetic ICI proteinoid to selectively inhibit tumor cell PD-L1 via a distinct endocytosis pathway between cancerous and non-cancerous cells (6).…”

“…In vivo experiments have shown that the biomimetic ICI proteinoid not only reactivates the anti-tumor immune response in a murine model of lung adenocarcinoma with coexisting idiopathic pulmonary fibrosis but also demonstrates a favorable safety profile by effectively eliminating any irAEs. This breakthrough broadens the boundaries of immunotherapy in lung cancer treatment (6).…”