Immunogenic Nanovesicle‐Tandem‐Augmented Chemoimmunotherapy via Efficient Cancer‐Homing Delivery and Optimized Ordinal‐Interval Regime

Abstract

The strategy of combining immune checkpoint inhibitors (ICIs) with anthracycline is recommended by clinical guidelines for the standard-of-care treatment of triple-negative breast cancer (TNBC). Nevertheless, several fundamental clinical principles are yet to be elucidated to achieve a great therapeutic effect, including cancer-homing delivery efficiency and ordinal-interval regime. Tumor-derived extracellular vesicles (TDEVs), as vectors for intratumoral intercellular communication, can encapsulate therapeutic agents and home tumors. However, PD-L1 overexpression in TDEVs leads to systemic immunosuppression during in vivo circulation, ultimately inhibiting intratumoral T activity. In this study, CRISPR/Cas9-edited Pd-l1 KO 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 disulfide-linked PD1-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. 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.

Sequential Targeting Hybrid Nanovesicles Composed of Chimeric Antigen Receptor T-Cell-Derived Exosomes and Liposomes for Enhanced Cancer Immunochemotherapy

“…In addition, previous studies have reported that PTX not only eliminated tumor cells directly but also induced the occurrence of ICD. − Hence, whether Lip-CExo@PTX enhanced the PTX-induced ICD effect was then investigated. The ICD effect was characterized by increased exposure of dying tumor cells to damage-associated molecular patterns (DAMPs), including calreticulin (CRT) on the surface of the tumor and high mobility group protein box 1 (HMGB1) and adenosine triphosphate (ATP) in the extracellular tissue fluid. − Thus, we examined the CRT expression of tumor cells coincubated with different drugs as well as the concentration levels of HMGB1 and ATP in the coincubated supernatant.…”

Liposome-Based Carriers for CRISPR Genome Editing

“…Despite early challenges of low transfection efficiency, liposome formulations have been developed to deliver siRNA, plasmid DNA, and mRNA for gene silencing, replacement, and protein expression [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. Surface modifications of liposomes with ligands, such as antibodies or peptides, have been a focus of research, enabling selective binding to specific receptors on target cells and improving delivery efficiency [ 12 , 13 , 35 , 36 , 37 , 38 ]. Additionally, stimuli-responsive liposomes were engineered to release their cargo in response to environmental cues, such as pH changes or ultrasound activity [ 37 , 39 , 40 , 41 ].…”

“…Hybrid liposomes are liposomes that incorporate other elements, such as mesoporous silica [ 12 ] or exosomes [ 38 ], to enhance their delivery efficiency. The specific composition of hybrid liposomes varies depending on the intended application.…”

Anthracycline‑induced delayed‑onset cardiac toxicity: A case report and literature review

“…Anthracycline (ANT) is a first-line chemotherapy drug with high clinical efficacy and a broad antitumor spectrum ( 1 ). Adriamycin, daunorubicin, epirubicin, mitoxantrone and nordoxorubicin all belong to the ANT family of agents that are commonly used in clinical practice and widely used for treating hematological and solid tumors ( 2 ). As the clinical application of ANTs has become more common, clinical side effects on the heart following ANT treatment are also becoming gradually understood.…”