Tumor-homing exosomes enable targeted delivery of siRNA and isoimperatorin for overcoming BTK inhibitor resistance in DLBCL

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma, but over one-third of patients relapse or develop refractory disease after first-line therapy. Novel therapeutic strategies are required to address persistent unmet clinical needs for DLBCL. This study aimed to develop an exosome-based drug delivery system for the targeted combination therapy of siRNA against Bruton's tyrosine kinase (BTK, an established therapeutic target in B cell lymphomas) and isoimperatorin (ISOIM, an active natural furanocoumarin showing anti-tumor effects) in DLBCL. Tumor exosomes were isolated as the delivery carrier. ISOIM/siBTK@Exosome was prepared by encapsulating ISOIM and si-BTK into exosome using electroporation. Cellular uptake, immune escape, targeted delivery efficiency, anti-lymphoma activity and biosafety of ISOIM/siBTK@Exosome were evaluated in two DLBCL cell lines and in tumor-bearing mice. ISOIM/siBTK@Exosome displayed significant anti-lymphoma activity compared to ISOIM@Exosome or siBTK@Exosome alone, demonstrating synergistic therapeutic role of ISOIM and si-BTK. Besides, ISOIM/siBTK@Exosome can accelerate T cells activation and prevent macrophage M2 polarization in vitro. Administration of ISOIM/siBTK@Exosome to tumor-bearing mice significantly inhibited tumor growth and prolonged survival. The ISOIM/siBTK@Exosome was biocompatible and biosafe in vivo without damage on the major organs in H&E staining. The prepared ISOIM/siBTK@Exosome may provide novel targeted therapeutic strategy to be applied in the clinical management of patients with DLBCL.