Exocytosis blockade of endoplasmic reticulum-targeted nanoparticle enhances immunotherapy

Abstract

Current endoplasmic reticulum (ER)-targeted strategies remain unsatisfactory, largely owing to limited ER accumulation and rapid exocytosis of nanodrugs after their ER arrival. Herein, we propose a brand-new ER-targeting strategy and demonstrate its underlying mechanism: (1) homologous cancer cell membrane-coated nanoparticle (HCC@NP) circumvents lysosome degradation via caveolae-related endocytosis and preferentially accumulates in ER-Golgi network due to the SNARE proteins existing on the surface of HCC@NP, allowing the recognition and binding of HCC@NP to ER-Golgi network; (2) loaded Brefeldin (BFA) is directed to its action site and block HCC@NP exocytosis from ER via coat protein type I (COPI) vesicle transport inhibition, achieving high-efficiency and long-term ER retention. This sequentially engaging and blocking ER-associated pathway approach induces potent ER stress-associated immunogenic cell death (ICD) events and recruits CD8+ T cells. Combination with anti-PD-L1 therapy overcomes adaptive PD-L1 enrichment following ICD induction. The rationally designed platform shows significant in vivo therapeutic efficacy by promoting anti-tumor immunity and reversing immunosuppression.