A mitochondria-anchored supramolecular photosensitizer as a pyroptosis inducer for potent photodynamic therapy and enhanced antitumor immunity

Abstract

Background The discovery of a potent photosensitizer with desirable immunogenic cell death (ICD) ability can prominently enhance antitumor immunity in photodynamic therapy (PDT). However, majority of commercially-available photosensitizers suffer from serious aggregation and fail to elicit sufficient ICD. Pyroptosis as a newly identified pattern for potent ICD generation is rarely disclosed in reported photosensitizers. In addition, the photosensitizer with excellent mitochondria-anchored ability evokes prominent mitochondria oxidative stress, and consequently induces ICD. Results Herein, a novel supramolecular photosensitizer LDH@ZnPc is reported, without complicated preparation, but reveals desirable pyroptosis-triggered ability with mitochondria anchoring feature. LDH@ZnPc is obtained through isolation of ZnPc using positive charged layered double hydroxides (LDH), and excellent mitochondria-anchored ability is achieved. More importantly, LDH@ZnPc-mediated PDT can effectively initiate gasdermin D (GSDMD)-dependent pyroptosis of tumor cells. In vitro and in vivo results verify robust ICD ability and potent tumor inhibition efficacy, and antitumor immunity towards distant tumor inhibition. Conclusions This study reveals that LDH@ZnPc can act as an excellent pyroptosis inducer with simultaneous mitochondria anchoring ability for enhancing photodynamic therapy and boosting antitumor immunity. Graphical Abstract

Photon-Controlled Pyroptosis Activation (PhotoPyro): An Emerging Trigger for Antitumor Immune Response

“…72 Compared to normal cells, tumor cells have a larger negative mitochondrial transmembrane potential, a feature that plays a critical role in their preferential accumulation of positively charged chemical entities, including certain drugs. 73 Appreciating this, a supramolecular PS named LDH@ZnPC was prepared by Wang et al 74 This system was designed to display effective mitochondrial localization and ROS production (Figure 4b-iii). By coupling positively charged lactate dehydrogenase (LDH) with zinc phthalocyanine (ZnPC), this LDH@ZnPc acted as a mitochondria-anchored pyroptosis inducer capable of boosting antitumor immunity.…”

Applications of supramolecular assemblies in drug delivery and photodynamic therapy

“…1,3-Diphenylisobenzofuran (DPBF) owing to its reaction with singlet oxygen is used as an indicator for extracellular generation of 1 O 2 for PSs. 21,22 1.2 Photosensitisers for photodynamic therapy Most of the PSs exhibit poor solubility and stability in aqueous media, which leads to aggregation 23,24 and accompanies photobleaching, resulting in relatively low PDT outcomes and ineffective therapy. 25 Due to lack of selectivity for tumor tissues over healthy tissues, majority of the PSs show dark toxicity and result in potential side effects.…”

“…Most of the PSs exhibit poor solubility and stability in aqueous media, which leads to aggregation 23,24 and accompanies photobleaching, resulting in relatively low PDT outcomes and ineffective therapy. 25 Due to lack of selectivity for tumor tissues over healthy tissues, majority of the PSs show dark toxicity and result in potential side effects.…”

Machine learning reveals PANoptosis as a potential reporter and prognostic revealer of tumour microenvironment in lung adenocarcinoma

“…Pyroptosis, apoptosis and necroptosis are three key programmed cell death pathways with certain molecular and genetic characteristics 10 . PANoptosis is an emerging concept that highlights the crosstalk and coordination between these three pathways 10,11 . It is able to eliminate intracellular pathogens and maintain homeostasis in the body 12,13 .…”

“…10 PANoptosis is an emerging concept that highlights the crosstalk and coordination between these three pathways. 10,11 It is able to eliminate intracellular pathogens and maintain homeostasis in the body. 12,13 Originally proposed in 2019, although scorch death, apoptosis and necroptosis have been described as distinct and independent pathways throughout the history of research, there is growing evidence of extensive interactions between these programmed cell death pathways.…”