A lipid nanoparticle-based peptide-proteolysis-targeting chimera degrades BCL6 for diffuse large B-cell lymphoma treatment.

B-cell lymphoma 6 (BCL6) is an attractive drug target for diffuse large B-cell lymphoma (DLBCL). This study aimed to create a lipid nanoparticle (LNP)-based peptide-proteolysis-targeting chimera (PROTAC), specifically BCL6-PROTAC, to develop effective strategies for treating DLBCL via targeted degradation of the BCL6 protein. Molecular docking, SPR and cellular thermal shift assays revealed that F1324 (Ac-LWYTDIRMSWRVP-OH) is a high-affinity BCL6-binding peptide. PROTAC LNPs were synthesized by modifying F1324 and pomalidomide aptamers onto LNPs via a covalent chemical reaction in a certain proportion. The LNPs were characterized using dynamic light scattering and transmission electron microscopy. The ligand ratio (F1324:pomalidomide) used to verify the optimal BCL6 degradation was 1:5, as determined using western blotting. In vitro and in vivo studies revealed that BCL6-PROTAC significantly inhibited the proliferation of DLBCL cells. Target-specific uptake was used to evaluate the accumulation of BCL6-PROTAC in vivo. Toxicity in normal tissues was detected using H&E staining and serum indices. Overall, we developed a PROTAC that exhibited persistent and excellent BCL6 degradation ability in DLBCL, with an excellent safety profile. Thus, our BCL6 degrader provides a complementary approach to existing clinical‑stage candidates.