Glutathione‐Depleting Organic Metal Adjuvants for Effective NIR‐II Photothermal Immunotherapy

Abstract

with immunotherapy, can directly cause tumor cell death in an immunogenic manner and work synergistically with immunotherapy to potentiate the immune response. [1] The therapeutic efficiency of PTI is often modest, owing to the inadequate immunogenicity of tumor cells and poor immune response. [2] PTT triggers immunogenic cell death (ICD) by releasing damage-associated molecular patterns (DAMPs) to induce dendritic cell (DC) maturation and increase T cell infiltration, thereby initiating the antitumor immune responses. [3] Evidence from recent studies has validated the pivotal role of reactive oxygen species (ROS) production and endoplasmic reticulum stress for the exposure of DAMPs. [3b,4] Therefore, the development of photothermal agents (PTAs) with effective ROS production capacities provides a promising direction for improving the immunogenicity of tumor cells. [5] The antioxidant system, mainly consisting of glutathione (GSH), can reduce ROS levels and lead to immunosuppression and attenuation of antitumor efficacy. [6] Therefore, it is imperative to exploit GSH-consuming PTAs to leverage the ICD effect of PTT and to serve as adjuvants to elevate immune responsiveness.Second near-infrared (NIR-II) (1000-1350 nm) PTAs, based on a variety of inorganic and organic materials, have recently attracted considerable attention owing to their advantages of deep tissue penetration, high maximum permission energy, and good sensitivity and signal-noise ratio. [7] So far, NIR-II PTAs have been explored in combination with immunoadjuvant therapy, genome editing-based therapy, or immune checkpoint blockade therapy to achieve effective PTI. [8] Among them, inorganic NIR-II PTAs, consisting of non-metallic materials, noble metals, and transition metal materials, exhibit good photothermal effects as well as tunable and controllable morphologies, but suffer from potential leakage and weak biodegradability. [9] Organic NIR-II PTAs, containing small-molecule photosensitizers, [10] semiconducting polymers, [11] and organic radicals, [12] exhibit low side-effects and good biocompatibility, [7] but sophisticated design and complex production requirements often hinder their applications. [10b,13] An organic metal is an organic material that possesses the electrical, magnetic, and optical properties of a metal while retaining the degradability, biocompatibility, adjustability, and processability associated Although photothermal immunotherapy (PTI) is a compelling strategy for tumor therapy, the development of promising photothermal agents to overcome the insufficient immunogenicity of tumor cells and the poor immune response encountered in PTI is still challenging. Herein, commercial small-molecule-based organic metal adjuvants (OMAs) are presented, with second near-infrared photoacoustic and photothermal properties as well as the ability to perturb redox homeostasis to potentiate immunogenicity and immune responsiveness. OMAs, assembled from charge-transfer complexes and characterized by a broad substrate scope, high accessibil...

Recent Advances in Engineering Nanomedicines for Second Near-Infrared Photothermal-Combinational Immunotherapy

“…The combination of reactive oxygen species (ROS) and NIR-II PTT-mediated heat generation for ICD induction and the promotion of immunotherapy has also been reported. As shown in Zhao’s group, small-molecule-based organic metal adjuvants (OMAs) with NIR-II photothermal properties and ROS-generating ability were developed for cancer therapy [ 55 ]. Such OMAs were constructed through the supramolecular assembly of commercially available donors and acceptors, showing excellent NIR-II photothermal properties and photoacoustic imaging performance via optimizing the constituting components.…”

A NIR-II light-modulated injectable self-healing hydrogel for synergistic photothermal/chemodynamic/chemo-therapy of melanoma and wound healing promotion

“…In particular, the PTT mediated by the second near-infrared (NIR-II, known as the second biological window with a spectrum range of 900–1400 nm) has attracted great attention. 8–10 It has shown deeper tissue penetration and a higher laser tolerance threshold than the first near-infrared (NIR-I, 650–900 nm) due to the reduced light absorption and scattering. However, the extensively applied nanosized photothermal therapeutic agents via systematic administration suffer from uncontrollable distribution and poorly targeted delivery, which compromised the therapeutic effect.…”

Crystal engineering of ferrocene-based charge-transfer complexes for NIR-II photothermal therapy and ferroptosis

“…Interestingly, the CTCs often not only display newly emerging properties but also retain the inherent properties of their constituent parts 11 . Therefore, by rationally selecting D/A building blocks like pH-sensitive tetramethylbenzidine, thiolsensitive tetracyanoquinodimethane derivatives, photosensitizer metalloporphyrin, H 2 O 2 -responsive metallocene, and so on, NIR-II PTT and other therapy modes including photodynamic therapy, ferrotherapy (or ferroptosis) and chemotherapy can be easily integrated into a nanoplatform for synergistic antitumor capacity to overcome intractable solid tumors 15,16 . Among them, ferroptosis, a new type of iron-dependent programmed cell death featured as the peroxidation of unsaturated fatty acid on the cell membrane, is an ideal candidate for the combination with PTT.…”

“…11 Therefore, by rationally selecting D/A building blocks like pH-sensitive tetramethylbenzidine, thiolsensitive tetracyanoquinodimethane derivatives, photosensitizer metalloporphyrin, H 2 O 2 -responsive metallocene, and so on, NIR-II PTT and other therapy modes including photodynamic therapy, ferrotherapy (or ferroptosis) and chemotherapy can be easily integrated into a nanoplatform for synergistic antitumor capacity to overcome intractable solid tumors. 15,16 Among them, ferroptosis, a new type of iron-dependent programmed cell death featured as the peroxidation of an unsaturated fatty acid on the cell membrane, is an ideal candidate for combination with PTT. On the one hand, ferroptosis can suppress the expression of heat shock proteins (HSPs) to improve the PTT efficiency, and on the other hand, PTT can promote ferroptosis achieving a synergistic effect.…”