Double-drug loading upconversion nanoparticles for monitoring and therapy of a MYC/BCL6-positive double-hit diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a systemic hematological malignancy. Herein, through whole exome sequencing (WES), we found that DLBCL genome changes and expression characteristics are associated with various immune cells. Lenalidomide (Len) is a leading candidate for the immunomodulatory treatment of multiple myeloma in the clinic. Inspired by lenalidomide as an immunomodulatory drug for the treatment of multiple myeloma, we constructed a multifunctional nanoplatform with therapeutic and imaging properties for DLBCL by co-loading lenalidomide and dexamethasone (Dex) with upconversion nanoparticles using a GSHsensitive linker (named as UCNPs-Len-Dex). In vitro cell experiments proved that the UCNPs-Len-Dex had good biocompatibility and obvious antitumor efficacy. UCNPs-Len-Dex also exhibited excellent anti-tumor efficacy and imaging properties in vivo. RNA sequencing showed that UCNPs-Len-Dex targeted and activated the E3 ligase of CRBN, resulting in IKZF1/3 degradation, which inhibited MYC/BCL6-positive DLBCL and maintained the stability of the immune microenvironment. Therefore, this study provided a new monitoring and therapeutic synergetic strategy for DLBCL.

Automated summary

This study discovered that DLBCL genome changes and expression characteristics are associated with various immune cells through whole exome sequencing. Inspired by lenalidomide as an immunomodulatory drug for multiple myeloma, the researchers constructed a multifunctional nanoplatform named UCNPs-Len-Dex, which demonstrated good biocompatibility and antitumor efficacy in vitro and in vivo. The RNA sequencing results indicated that UCNPs-Len-Dex targeted and activated the E3 ligase of CRBN, inhibiting MYC/BCL6-positive DLBCL and maintaining immune microenvironment stability.