MDSC-targeting gold nanoparticles enhance PD-1 tumor immunotherapy by inhibiting NLRP3 inflammasomes.

Myeloid-derived suppressor cells (MDSCs) play a crucial role in the immune escape mechanisms that limit the efficacy of immunotherapeutic strategies. In the tumor microenvironment, NLRP3 inflammasome-driven Interleukin-1ß (IL-1ß) production serves to dampen antitumor immune responses, promoting tumor growth, progression, and immunosuppression. In this study, we revealed that gold nanoparticles (Au NPs) with a size of 30 nm disrupted NLRP3 inflammasome, but not other inflammasomes, in bone marrow-derived macrophages through abrogating NLRP3-NEK7 interactions mediated by reactive oxygen species (ROS). Density functional theory (DFT) calculations provided insights into the mechanism underlying the exceptional ROS scavenging capabilities of Au NPs. Additionally, when coupled with H6, a small peptide targeting MDSCs, Au NPs demonstrated the capacity to effectively reduce IL-1ß levels and diminish the MDSCs population in tumor microenvironment, leading to enhanced T cell activation and increased immunotherapeutic efficacy in mouse tumor models that are sensitive and resistant to PD-1 inhibition. Our findings unraveled a novel approach wherein peptide-modified Au NPs relieved the suppressive impact of the tumor microenvironment by inhibiting MDSCs-mediated IL-1ß release, which is the first time reported the employing a nanostrategy at modulating MDSCs to reverse the immunosuppressive microenvironment and may hold promise as a potential therapeutic agent for cancer immunotherapy.

AIE-enabled transfection-free identification and isolation of viable cell subpopulations differing in the level of autophagy.

ABBREVIATIONS: 3-MA, 3-methyladenine; AIE, aggregation-induced emission; AIEgens, aggregation-induced emission luminogens; ATG5, autophagy related 5; BMDM, bone marrow-derived macrophage; CQ, chloroquine; DiD, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine perchlorate; DiO, 3,3'-dioctadecyloxacarbocyanine perchlorate; DMSO, dimethyl sulfoxide; d-THP-1, differentiated THP-1; FACS, fluorescence activated cell sorting; FBS, fetal bovine serum; FCCP, carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone; GABARAP, GABA type A receptor-associated protein; GFP, green fluorescent protein; HBSS, Hanks' balanced salt solution; HPLC, high-performance liquid chromatography; HRP, horseradish peroxidase; IL1B, interleukin 1 beta; KT, an AIE probe composed of a cell-penetrating peptide and an AIEgen tetraphenyl ethylene; LC3-II, lipidated LC3; LDH, lactate dehydrogenase; LIR, LC3-interacting region; LKR, engineered molecular probe composed of an LC3-interacting peptide, a cell-penetrating peptide and a non-AIE fluorescent molecule rhodamine; LKT, engineered molecular probe composed of an LC3-interacting peptide, a cell-penetrating peptide and an AIEgen tetraphenyl ethylene; LPS, lipopolysaccharide; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MEF, mouse embryonic fibroblast; mRFP, monomeric red fluorescent protein; NHS, N-hydroxysuccinimide; NLRP3, NLR family pyrin domain containing 3; PBS, phosphate-buffered saline; PCC, pearson's correlation coefficient; PL, photoluminescence; PMA, phorbol 12-myristate 13-acetate; RAP, rapamycin; RIM, restriction of intramolecular motions; s.e.m., standard error of the mean; SPR, surface plasmon resonance; SQSTM1/p62, sequestosome 1; TAX1BP1, Tax1 binding protein 1; TPE, tetraphenylethylene; TPE-yne, 1-(4-ethynylphenyl)-1,2,2-triphenylethene; Tre, trehalose; u-THP-1: undifferentiated THP-1; UV-Vis, ultraviolet visible.

Precise pancreatic cancer therapy through targeted degradation of mutant p53 protein by cerium oxide nanoparticles.

BACKGROUND: In a significant proportion of cancers, point mutations of TP53 gene occur within the DNA-binding domain, resulting in an abundance of mutant p53 proteins (mutp53) within cells, which possess tumor-promoting properties. A potential and straightforward strategy for addressing p53-mutated cancer involves the induction of autophagy or proteasomal degradation. Based on the previously reported findings, elevating oxidative state in the mutp53 cells represented a feasible approach for targeting mutp53. However, the nanoparticles previous reported lacked sufficient specificity of regulating ROS in tumor cells, consequently resulted in unfavorable toxicity in healthy cells. RESULTS: We here in showed that cerium oxide CeO2 nanoparticles (CeO2 NPs) exhibited an remarkable elevated level of ROS production in tumor cells, as compared to healthy cells, demonstrating that the unique property of CeO2 NPs in cancer cells provided a feasible solution to mutp53 degradation. CeO2 NPs elicited K48 ubiquitination-dependent degradation of wide-spectrum mutp53 proteins in a manner that was dependent on both the dissociation of mutp53 from the heat shock proteins Hsp90/70 and the increasing production of ROS. As expected, degradation of mutp53 by CeO2 NPs abrogated mutp53-manifested gain-of-function (GOF), leading to a reduction in cell proliferation and migration, and dramatically improved the therapeutic efficacy in a BxPC-3 mutp53 tumor model. CONCLUSIONS: Overall, CeO2 NPs increasing ROS specifically in the mutp53 cancer cells displayed a specific therapeutic efficacy in mutp53 cancer and offered an effective solution to address the challenges posed by mutp53 degradation, as demonstrated in our present study.

Enhancing anti-tumor effect of ultrasensitive bimetallic RuCu nanoparticles as radiosensitizers with dual enzyme-like activities.

Radiotherapy (RT), through the generation of reactive oxygen species (ROS) and DNA damage to tumor cells caused by high-energy irradiation, has been a widely applied cancer treatment strategy in clinic. However, the therapeutic effect of traditional RT is restricted by the insufficient radiation energy deposition and the side effects on normal tissues. Recently, multifunctional nano-formulations and synergistic therapy has been developed as attractive strategies for used to enhancing the efficacy and safety of RT. Herein, we show that a bimetallic nanozyme (copper-modified ruthenium nanoparticles, RuCu NPs), containing the high atomic number (Z) element Ru as a novel radiosensitizer, offers an ideal solution to RT sensitization, with ultrasensitive peroxidase (POD)-like activity and catalase (CAT)-like activity. Density functional theory (DFT) calculations also clarified the optimal POD-like catalytic ratio of RuCu NPs and further revealed the mechanism of its supper catalytic activity. Under X-ray exposure, RuCu NPs coated with poly(ethylene glycol) (PEG) exhibited simultaneously improved the ROS production and relieved tumor hypoxia in the acid tumor microenvironment (TME), and demonstrated remarkable therapeutic efficacy in the MDA-MB-231 breast cancer model. Our results provide a proof-of-concept for a RT sensitization strategy, which combine the intrinsic nature of high-Z element and the advantages of nanozymes to overcome the tricky drawbacks existed in radiotherapy, and further open a new direction of exploring novel nanozyme-based strategies for tumor catalytic therapy and synergistic radiotherapy.