Immunogenic Nanovesicle-Tandem-Augmented Chemoimmunotherapy Via Efficient Cancer-Homing Delivery And Optimized Ordinal-Interval Regime

Objective:Triple-negative breast cancer(TNBC)has poor prognosis and unsatisfactory therapeutic effect due to the absence of endocrine targets and its invasiveness and drug resistance.It is hoped to improve the safety and effectiveness of chemoimmunotherapy by constructing a targeted artificial hybrid-biodrug delivery system and a targeted drug delivery system sensitive to reduction in tumor microenvironment,using ICD effect and tumor immune response.Methods:T-DOX with tumor targeting was constructed by using TDEVs,a natural product of cells,as a drug carrier.The ICD-inducing effect of T-DOX and the up-regulation effect of PD-L1 expression were used to regulate the tumor microenvironment.Optimize the ICIs drug delivery and release system.The immunotherapy administration regimen was optimized.Results:In this study,CRISPR/Cas9-edited PD-L1KO TDEV-fusogenic anthracycline doxorubicin(DOX)liposomes with high drug encapsulation(97%)are fabricated,which homologously deliver DOX to breast cancer cells to intensify the immunogenic response and induce PD-L1 overexpression in the tumor.By setting the stage for sensitizing tumors to ICIs,sequential treatment with disulfifide-linkedPD1-cross-anchored TDEVs nanogels at one-day interval could sustainably release PD1 in the tumor,triggering a high proportion of effector T cell-mediated destruction of orthotopic and metastatic tumors without off-target side effects in the 4T1-bearing TNBC mouse model.Conclusion:Such a TDEV-tandem-augmented chemoimmunotherapeutic strategy with efficient cancer-homing delivery capacity and optimized ordinal-interval regime provides a solid foundation for developing chemoimmunotherapeutic formulations for TNBC therapy at the clinical level.