Breaking Spatiotemporal Barriers of Immunogenic Chemotherapy via an Endoplasmic Reticulum Membrane-Assisted Liposomal Drug Delivery

Abstract

Immunogenic chemotherapy is a promising approach in cancer treatment, but the number of drugs capable of inducing immunogenic cell death is limited, and chronic immunogenic exposure can delay antitumor immune response and be counteracted by immunosuppressive factors. In this study, we used single-cell and multilevel analyses to highlight the critical importance of the first exposure to calreticulin (CRT) in eliciting immunogenicity. We then developed the ERASION (endoplasmic reticulum (ER) membrane to assist (AS) the presentation of intrinsic onco-immunogenicity (ION)) strategy, leveraging the high expression of functional proteins, including CRT, on the ER membrane. ER membrane-coated liposome (ER@PLip) was able to target the tumor and immune effectors and promoted dendritic cell maturation and T cell infiltration. This enabled eliciting an immunogenic effect from a nonimmunogenic chemotherapeutic drug. By utilizing the ER membrane-associated STING protein, ERASION enabled activating the STING pathway and the generation of adaptive antitumor immunity. This study presents a potential universal platform for integrating traditional chemotherapy and therapeutic modalities.

Chemoimmunotherapeutic Nanogel for Pre- and Postsurgical Treatment of Malignant Melanoma by Reprogramming Tumor-Associated Macrophages

“…Besides, H&E and TUNEL staining assays were performed to further verify the antitumor performance after different treatments, which showed that D@HPMNG could efficaciously destroy the tumor structure, damage tumor cell nucleus, and induce tumor cell apoptosis (Figure 3K, Figure S9). 45 In addition, neither apparent body weight changes nor pathological alternation of the major organs, especially the cardiotoxicity induced by DOX, was identified after the whole treatment, proving the good biosafety of prepared nanogels in vivo (Figures S10 and S11). 46,47 Meanwhile, the survival rate of mice suffering from melanoma was also prolonged after treatment with D@ HPMNG, only 20% of mice died in the D@HPMNG group, whereas no mice survived in the control group after 50 days (Figure S12).…”

Black Phosphorus Quantum Dot Loaded Bioinspired Nanoplatform Synergized with aPD-L1 for Multimode Cancer Immunotherapy

“…Black phosphorus quantum dot (BPQD) is a novel near-infrared (NIR) photosensitizer with good biocompatibility, and excellent photothermal/photodynamic properties. − It is worth noting that the hyperthermia induced by photothermal therapy (PTT) and the cytotoxic reactive oxygen species (ROS) generated by photodynamic therapy (PDT) are capable of triggering tumor cell apoptosis and necrosis, which can directly kill tumors. − Meanwhile, the application of phototherapy can induce the immunogenic cell death (ICD) of tumor cells, which facilitates the release of tumor-associated antigens (TAAs) and damage-associated patterns (DAMPs) including calreticulin (CRT) exposure, high mobility group box-1 protein (HMGB1) and ATP release, eventually promoting the maturation of dendritic cells (DCs) and T cell activation. − In recent years, many studies have verified the broad antitumor effectiveness of metformin (Met) such as its chemotherapeutic effects by activating adenosine 5′-monophosphate-activated protein kinase (AMPK) pathway, which could inhibit tumor angiogenesis, arrest tumor cell cycle, and regulate tumor metabolism, etc. − Interestingly, several studies also demonstrated the immunomodulatory effect of Met in reprogramming tumor-associated macrophage (TAM) phenotypes and increasing the intratumoral infiltrations of cytotoxic T cells, suggesting its potential in antitumor immunotherapy. − In our previous work, PolyMetformin (PM), which shares the similar antitumor mechanisms as Met, was synthesized by covalently binding chitosan with dicyandiamide via an addition reaction . In this present study, cationic PM was interacted with anionic BPQD to form a stable core through electrostatic interaction, which was encapsulated in the hydrophilic lumen of RTM-coated liposomes (RTL).…”