Rationally Integrated Precise ER‐Targeted and Oxygen‐Compensated Photodynamic Immunostimulant for Immunogenicity‐Boosted Tumor Therapy

Abstract

Notwithstanding that immunotherapy has made eminent clinical breakthroughs, activating the immunogenicity and breaking the immunosuppressive tumor microenvironment (ITME) remains tempting yet challenging. Herein, a customized‐designed immunostimulant was engineered for attenuating ITME and eliciting an immune response to address this challenge head‐on. This immunostimulant was equipped with dual silica layers coated upconversion nanoparticles (UCNPs) as nanocarriers modified with N‐p‐Tosylglycine, in which the dense silica for chlorin e6 (Ce6) and the glutathione (GSH)‐responsive degradable silica for loading resveratrol (RES) (UCNPs@SiO2‐Ce6@MON(RES)@ER (UCSMRER)). On the one hand, UCSMRER was positioned accurately in the endoplasmic reticulum (ER) guided by the ER‐targeted molecular N‐p‐Tosylglycine. This precise ER‐targeted photodynamic therapy (PDT) could generate reactive oxygen species (ROS) in situ under the 980 nm laser irradiation, which not only induced severe cell death directly but also caused intense ER stress‐based immunogenic cell death (ICD) effects, triggering a tumor immune response. On the other hand, tumor hypoxia aggravated by the PDT process was effectively alleviated by RES released on‐demand, which reduced oxygen consumption by impairing the mitochondrial electron transport chain (ETC). This integrated precise ER‐targeted and oxygen‐compensated strategy maximized the PDT effect and potentiated ICD‐associated immunotherapy, which availed to attenuate ITME, activate tumor immunogenicity and further magnify anti‐tumor effect. This innovative concept about PDT and immunotherapy sheds light on the cancer‐related clinical application.This article is protected by copyright. All rights reserved

Molecularly Targeted Lanthanide Nanoparticles for Cancer Theranostic Applications

“…), as well as to detect, in time and space, As mentioned above, luminescence imaging and drug delivery using LnNPs is another area where preclinical studies have demonstrated their theranostic potential. For example, the UCNPs@polyHPMA-5FU nanosystem is used for luminescence imaging and selective cancer drug delivery [37]. Also relevant is the development of target-specific biomolecules coated on Yb/Er/Ho enriched NaGdF 4 nanoparticles as NIR-II systems for luminescence imaging, MR imaging, X-ray CT imaging, and photodynamic therapy (Table 2).…”

“…UCNPs@mSiO 2 -Ce6-GPC3 for PDT in vitro and in vivo. [18,[35][36][37][38][39] Reverse micelle method for hydrophobic ligands.…”

Blood–Brain Barrier Penetrating Nanovehicles for Interfering with Mitochondrial Electron Flow in Glioblastoma

“…Manipulating the mitochondrial electron transport chain (ETC) enhances tumor immunogenicity, rendering immune-evasive tumors vulnerable to immune surveillance. − Dysfunction of complex II (CII) leads to the abnormal transfer of electrons in the ETC, an increase in succinate production and upregulation of the expression of major histocompatibility complex (MHC) and antigen processing and presentation (APP) genes, making GBM more susceptible to cytotoxic T-cell recognition and elimination. − Moreover, mitochondrial DNA (mtDNA) possesses CpG motifs, making them vulnerable to mitochondrial reactive oxygen species (mtROS). , Here, we synthesized iridium photosensitizer (IrPS) that electrostatically bind to GBM cell mitochondria by the positive charge after illumination by two-photon light, induce ETC damage, and produce mtROS to oxidize mtDNA. Oxidized mtDNA in GBM can activate the STING pathway, thereby enhancing GBM immune responsiveness and subsequently activating both innate and adaptive immunity.…”

“Three Musketeers” Enhances Photodynamic Effects by Reducing Tumor Reactive Oxygen Species Resistance

“…Simultaneously, the degradation of the MON led to the release of CQ and CHCA that achieve different goals. First, autophagy inhibitor CQ can inhibit autophagy of tumor cells because it can block the fusion of autophagosomes and lysosomes. , Second, CHCA inhibited lactic acid metabolism by limiting the uptake of lactic acid by tumor cells through the inhibition of MCT1, thereby reducing the intracellular lactic acid concentration. − Finally, the reduction of intracellular GSH and the inhibition of lactic acid uptake made tumor cells lose the ability to reduce ROS concentration, while the blocking of autophagy led to the failure of tumor cells to resist ROS damage. Like the “three musketeers”, the three functions of UCNPs@MON@CQ/CHCA@HA broke the tolerance of tumor cells to ROS from different angles, thereby improving the PDT effect and ultimately killing tumor cells.…”