Dual‐Responsive Supramolecular Polymeric Nanomedicine for Self‐Cascade Amplified Cancer Immunotherapy

Abstract

Insufficient tumor immunogenicity and immune escape from tumors remain common problems in all tumor immunotherapies. Recent studies have shown that pyroptosis, a form of programmed cell death that is accompanied by immune checkpoint inhibitors, can induce effective immunogenic cell death and long‐term immune activation. Therapeutic strategies to jointly induce pyroptosis and reverse immunosuppressive tumor microenvironments are promising for cancer immunotherapy. In this regard, a dual‐responsive supramolecular polymeric nanomedicine (NCSNPs) to self‐cascade amplify the benefits of cancer immunotherapy is designed. The NCSNPs are formulated by β‐cyclodextrin coupling nitric oxide (NO) donor, a pyroptosis activator, and NLG919, an indoleamine 2,3‐dioxygenase (IDO) inhibitor, and self‐assembled through host–guest molecular recognition and hydrophobic interaction to obtain nanoparticles. NCSNPs possess excellent tumor accumulation and bioavailability attributed to ingenious supramolecular engineering. The study not only confirms the occurrence of NO‐triggered pyroptosis in tumors for the first time but also reverses the immunosuppressive microenvironment in tumor sites via an IDO inhibitor by enhancing the infiltration of cytotoxic T lymphocytes, to achieve remarkable inhibition of tumor proliferation. Thus, this study provides a novel strategy for cancer immunotherapy.

A Cascade-Amplified Pyroptosis Inducer: Optimizing Oxidative Stress Microenvironment by Self-Supplying Reactive Nitrogen Species Enables Potent Cancer Immunotherapy

“…These results suggested strong synergistic effects between CPT and SNAP when the ratio reached 1:250. For the therapeutic regimen in this work, it is expected that while efforts to capitalize on the induction of pyroptosis by both endogenous mtROS stimulated by the released CPT 51 and the released NO, 23 the NO can utmostly react with mtROS to maximize the generation of RNS, optimizing the utilization rate of ROS for amplifying pyroptosis-evoked immune response through the facilitation of RONS-NO synergy (Figure S22). Flow cytometry was used to evaluate the RNS production of the CSC CPT/SNAP series, and CSC CPT/SNAP (1:250) had the highest levels of RNS (Figure 2c).…”

“…As a biological messenger molecule, nitric oxide (NO) plays an important role in the physiology and pathophysiology system. Early studies focused on the proclivity of NO to sensitize cells to apoptosis through multiple pathways, such as elevation of oxidative stress, destruction of mitochondria, and inhibition of DNA synthesis/repair. , Recently, NO has also been shown to induce pyroptosis. − Interestingly, cellular ROS and NO have a close relationship, where they are produced with a few dozen microns of each other to form reactive nitrogen species (RNS) in a diffusion-controlled reaction coefficient (6.7 × 10 9 M –1 s –1 ) without enzymatic catalysis. , RNS are another kind of important component of the free radical active substance . It can aggravate damage to tumor cells.…”

“…CSC CPT/SNAP realized the simultaneous release of CPT and NO through the cleavage of the disulfide bond and the binding to glutathione (GSH), respectively (Scheme b). Pyroptosis is triggered by both endogenous mitochondrial ROS (mtROS) stimulated by the released CPT and the released NO. − Concomitantly, the rapid reaction between these elements generated endogenous RNS, which optimized the utilization rate of ROS and sustainably induced pyroptosis, achieving a longer-lasting immunotherapy. Given these advantages, our work offers an innovative perspective on cancer immunotherapy via RNS self-sufficiency.…”