Engineered Enzyme-Loaded Erythrocyte Vesicles Precisely Deprive Tumoral Nutrients to Induce Synergistic Near-Infrared-II Photothermal Therapy and Immune Activation

Abstract

Starvation therapy has been considered a promising strategy in cancer treatment for altering the tumor microenvironment (TME) and causing a cascade of therapeutic effects. However, it is still highly challenging to establish a therapeutic strategy for precisely and potently depriving tumoral nutrition. In this study, a glucose oxidase (GOx) and thrombin-incorporated erythrocyte vesicle (EV) with cyclic (Arg-Gly-Asp) (cRGD) peptide modification, denoted as EV@RGT, were synthesized for precisely depriving tumoral nutrition and sequentially inducing second near-infrared region (NIR-II) photothermal therapy (PTT) and immune activation. The EV@RGT could specifically accumulate at the tumor site and release the enzymes at the acidic TME. The combination of GOx and thrombin exhausts tumoral glucose and blocks the nutrition supply at the same time, resulting in severe energy deficiency and reactive oxygen species (ROS) enrichment within tumor cells. Subsequently, the abundant clotted erythrocytes in tumor vessels present outstanding localized NIR-II PTT for cancer eradication owing to the hemoglobin. Furthermore, the abundant ROS generated by enhanced starvation therapy repolarizes resident macrophages into the antitumor M1 phenotype via a DNA damage-induced STING/NF-κB pathway, ultimately contributing to tumor elimination. Consequently, the engineered EV@RGT demonstrates powerful antitumor efficiency based on precise nutrition deprivation, sequential NIR-II PTT, and immune activation effect. This work provides an effective strategy for the antitumor application of enzyme-based reinforced starvation therapy.

Free Radicals Generated in Perfluorocarbon–Water (Liquid–Liquid) Interfacial Contact Electrification and Their Application in Cancer Therapy

“…The results of hematoxylin and eosin (H&E) and transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining verified the ROS-mediated tumor killing, and the HP NPs+US group showed more severe apoptosis than other three groups . Ki67 staining further demonstrated that the HP NPs+US group severely affected the proliferation of tumor cells. , All of these results confirm that the ROS generated in liquid–liquid contact exhibit excellent tumor suppressive ability.…”

“…Briefly, ROS induces ICD of tumor cell to release tumor-associated antigens, which can attract the recruitment of APCs, and present antigenic peptides to T cells to trigger an adaptive immune response to reverse tumor immunosuppressive microenvironment . As shown in Figure a,b, macrophages (CD11b + ) of treated tumor-bearing mice aggregate at the tumor site and regulate the transition of tumor-associated macrophages (TAMs) from M2-like phenotype to M1-like phenotype (Figure c,d). , The number of M1-TAMs in the HP NPs+US group was approximately 3.1-fold higher than that of the Control group, while the number of M2-TAMs decreased by 53.6% compared to the Control group, demonstrating that the reversal of macrophage phenotype successfully converted the tumor microenvironment from “cold” to “hot”. , In addition, as one of the important antigen-presenting cells, DCs (CD11c + ) also massively infiltrate the tumor sites of tumor-bearing mice after treatment (Figure e), integrate antigen signals from tumor cells, and migrate to mature in tumor-draining lymph nodes (TDLNs) to present antigen to T cells. , Thus, TDLNs in the treated groups were determined by FCAS to study the maturation of DCs (Figure f,g) . As expected, there was no significant difference in the number of mature DCs (CD80 + CD86 + ) in the three groups, Control, Control+US, and HP NPs.…”

Comment on “Engineered Enzyme-Loaded Erythrocyte Vesicles Precisely Deprive Tumoral Nutrients to Induce Synergistic Near-Infrared-II Photothermal Therapy and Immune Activation”

“…C omment on "Engineered Enzyme-Loaded Erythrocyte Vesicles Precisely Deprive Tumoral Nutrients to Induce Synergistic Near-Infrared-II Photothermal Therapy and Immune Activation" published in ACS Nano. 1 The study presents a fascinating approach for targeting tumoral nutrients and inducing synergistic near-infrared-II (NIR-II) photothermal therapy (PTT) and immune activation using engineered erythrocyte vesicles (EVs) loaded with glucose oxidase (GOx) and thrombin. The combination of nutrient deprivation, localized PTT, and immune activation shows promising results for antitumor therapy.…”

“…EV@RGT exhibits the ability to selectively accumulate at the tumor site and release these enzymes within the acidic tumor microenvironment (TME). 1 Recent studies have highlighted some limitations of RGD (arginine-glycine-aspartate) targeting in tumor therapy. These include challenges in systemic delivery, where modifications like PEGylation can reduce cellular internalization and trafficking to the nucleus, impacting the efficiency of adenoviruses (Ads) used in cancer gene therapy.…”

“…EV@RGT has been designed for the precise deprivation of tumoral nutrients and subsequent induction of second near-infrared region (NIR-II) photothermal therapy (PTT) and immune activation. EV@RGT exhibits the ability to selectively accumulate at the tumor site and release these enzymes within the acidic tumor microenvironment (TME) …”