Avidity‐Based Capture of PD‐L1‐Expressing Exosomes via Dendrimer–Peptide Conjugates: A Nanoengineered Platform for Enhanced Prediction of Immunotherapy Response

Abstract

A major challenge in immunotherapy is the inability to reliably predict patient responses due to the lack of robust biomarkers. Programmed cell death‐ligand 1 (PD‐L1)–expressing exosomes represent a promising biomarker candidate; however, existing detection platforms lack the sensitivity and specificity required for clinical translation. It is hypothesized that an avidity‐based capture strategy utilizing dendrimer‐mediated multivalent binding will effectively enhance molecular avidity and improve the selective capture of PD‐L1‐expressing exosomes. Supporting this hypothesis, atomic force microscopy (AFM) revealed that dendrimer–peptide conjugates synthesized using generation 7 poly(amidoamine) dendrimers (G7‐pPDL1) exhibited ≈2.48‐fold higher binding avidity than conventional anti‐PD‐L1 antibodies (aPD‐L1), attributed to multivalent interactions. This increased avidity led to enhanced in vitro specificity and enabled 1.55‐fold greater sensitivity in capturing PD‐L1‐expressing exosomes, compared to aPD‐L1. Clinical validation using serum samples from patients undergoing immune checkpoint inhibitor therapy demonstrated that PD‐L1‐expressing exosomes captured using the G7‐pPD‐L1 surface more accurately predicted treatment response and outperformed tissue‐based PD‐L1 scoring in prognostic value. Additionally, this platform is compatible with existing biosensing technologies and enables real‐time exosome detection with a limit of detection as low as 9.6 × 10¹ vesicles mL⁻¹. Taken together, these findings highlight the versatility and clinical promise of this avidity‐based capture strategy for advancing precision immunotherapy.