Monitoring the Mitochondrial Viscosity Changes During Cuproptosis with Iridium(III) Complex Probe via In Situ Phosphorescence Lifetime Imaging.

Cuproptosis is a novel copper-dependent form of programmed cell death, displaying important regulatory functions in many human diseases, including cancer. However, the relationship between the changes in mitochondrial viscosity, a key factor associated with cellular malfunction, and cuproptosis is still unclear. Herein, we prepared a phosphorescent iridium (Ir) complex probe for precisely monitoring the changes of mitochondrial viscosity during cuprotosis via phosphorescence lifetime imaging. The Ir complex probe possessed microsecond lifetimes (up to 1 µs), which could be easily distinguished from cellular autofluorescence to improve the imaging contrast and sensitivity. Benefiting from the long phosphorescence lifetime, excellent viscosity selectivity, and mitochondrial targeting abilities, the Ir complex probe could monitor the increase in the mitochondrial viscosity during cuproptosis (from 46.8 to 68.9 cP) in a quantitative manner. Moreover, through in situ fluorescence imaging, the Ir complex probe successfully monitored the increase in viscosity in zebrafish treated with lipopolysaccharides or elescolomol-Cu2+, which were well-known cuproptosis inducers. We anticipate that this new Ir complex probe will be a useful tool for in-depth understanding of the biological effects of mitochondrial viscosity during cuproptosis.

Iridium(III)-Based PD-L1 Agonist Regulates p62 and ATF3 for Enhanced Cancer Immunotherapy.

Anti-PD-L1 immunotherapy, a new lung cancer treatment, is limited to a few patients due to low PD-L1 expression and tumor immunosuppression. To address these challenges, the upregulation of PD-L1 has the potential to elevate the response rate and efficiency of anti-PD-L1 and alleviate the immunosuppression of the tumor microenvironment. Herein, we developed a novel usnic acid-derived Iridium(III) complex, Ir-UA, that boosts PD-L1 expression and converts "cold tumors" to "hot". Subsequently, we administered Ir-UA combined with anti-PD-L1 in mice, which effectively inhibited tumor growth and promoted CD4+ and CD8+ T cell infiltration. To our knowledge, Ir-UA is the first iridium-based complex to stimulate the expression of PD-L1 by explicitly regulating its transcription factors, which not only provides a promising platform for immune checkpoint blockade but, more importantly, provides an effective treatment strategy for patients with low PD-L1 expression.

Identification of Cellular Protein Targets of a Half-Sandwich Iridium(III) Complex Reveals Its Dual Mechanism of Action via Both Electrophilic and Oxidative Stresses.

Identification of intracellular targets of anticancer drug candidates provides key information on their mechanism of action. Exploiting the ability of the anticancer (C∧N)-chelated half-sandwich iridium(III) complexes to covalently bind proteins, click chemistry with a bioorthogonal azido probe was used to localize a phenyloxazoline-chelated iridium complex within cells and profile its interactome at the proteome-wide scale. Proteins involved in protein folding and actin cytoskeleton regulation were identified as high-affinity targets. Upon iridium complex treatment, the folding activity of Heat Shock Protein HSP90 was inhibited in vitro and major cytoskeleton disorganization was observed. A wide array of imaging and biochemical methods validated selected targets and provided a multiscale overview of the effects of this complex on live human cells. We demonstrate that it behaves as a dual agent, inducing both electrophilic and oxidative stresses in cells that account for its cytotoxicity. The proposed methodological workflow can open innovative avenues in metallodrug discovery.

[Imaging of In Vivo Oxygen Tension Based on Phosphorescence Lifetime Microscopy].

Molecular oxygen plays essential roles in aerobic organisms as a terminal electron acceptor in the electron transport chain in mitochondria. The intracellular oxygen concentration of the entire body is strictly regulated by a balance between the supply of oxygen from blood vessels and the consumption of oxygen in mitochondria. The disruption of oxygen homeostasis in the body often results in serious pathologies such as cancer, cerebral infarction, and chronic kidney disease, and thus considerable effort has been devoted to the development of suitable techniques allowing the qualitative and quantitative detection of tissue oxygen levels. This review focuses on recent advances in the visualization of oxygen levels in tissue based on phosphorescence lifetime measurements using exogenously small molecular oxygen probes. Specially, I introduce the principle of oxygen sensing by means of phosphorescence quenching, recent advances in intracellular and intravascular oxygen probes based on iridium(III) complexes, a system for measuring phosphorescence lifetime combined with confocal scanning microscopy, and the applications of these technologies to in vivo oxygen measurements, emphasizing the usefulness of iridium(III) complexes as biological oxygen probes.

Designing a Mitochondria-Targeted Theranostic Cyclometalated Iridium(III) Complex: Overcoming Cisplatin Resistance and Inhibiting Tumor Metastasis through Necroptosis and Immune Response.

To develop a potential theranostic metal agent to reverse the resistance of cancer cells to cisplatin and effectively inhibit tumor growth and metastasis, we proposed to design a cyclometalated iridium (Ir) complex based on the properties of the tumor environment (TME). To the end, we designed and synthesized a series of Ir(III) 2-hydroxy-1-naphthaldehyde thiosemicarbazone complexes by modifying the hydrogen atom(s) of the N-3 position of 2-hydroxy-1-naphthaldehyde thiosemicarbazone compounds and the structure of cyclometalated Ir(III) dimers and then investigated their structure-activity and structure-fluorescence relationships to obtain an Ir(III) complex (Ir5) with remarkable fluorescence and cytotoxicity to cancer cells. Ir5 not only possesses mitochondria-targeted properties but also overcomes cisplatin resistance and effectively inhibits tumor growth and metastasis in vivo. Besides, we confirmed the anticancer mechanisms of Ir5 acting on different components in the TME: directly killing liver cancer cells by inducing necroptosis and activating the necroptosis-related immune response.

Iridium(III) complexes decorated with silicane-modified rhodamine: near-infrared light-initiated photosensitizers for efficient deep-tissue penetration photodynamic therapy.

Meeting the demand for efficient photosensitizers in photodynamic therapy (PDT), a series of iridium(III) complexes decorated with silicane-modified rhodamine (Si-rhodamine) was meticulously designed and synthesized. These complexes demonstrate exceptional PDT potential owing to their strong absorption in the near-infrared (NIR) spectrum, particularly responsive to 808 nm laser stimulation. This feature is pivotal, enabling deep-penetration laser excitation and overcoming depth-related challenges in clinical PDT applications. The molecular structures of these complexes allow for reliable tuning of singlet oxygen generation with NIR excitation, through modification of the cyclometalating ligand. Notably, one of the complexes (4) exhibits a remarkable ROS quantum yield of 0.69. In vivo results underscore the efficacy of 4, showcasing significant tumor regression at depths of up to 8.4 mm. This study introduces a promising paradigm for designing photosensitizers capable of harnessing NIR light effectively for deep PDT applications.

Light-harvesting iridium (III) complex-sensitized NiO photocathode for photoelectrochemical bioanalysis.

A novel iridium (III) complex bearing boron dipyrromethene (Bodipy) as the light-harvesting antenna has been synthesized and is firstly employed as photosensitizer to assemble a dye-sensitized NiO photocathode. The assembled photocathode exhibits significantly improved photoelectrochemical (PEC) performance. Integrating the prepared photocathode with hybridization chain reaction (HCR)--based signal amplification strategy, a cathodic PEC biosensor is proposed for the detection of microRNA-133a (miRNA-133a). In the presence of the target, HCR is triggered to form long duplex concatamers on the photocathode, which allows numerous manganese porphyrins (MnPP) to bind in the dsDNA groove. With the help of H2O2, MnPP with peroxidase-like activity catalyzes 4--chloro-1-naphthol (4-CN) to produce benzo--4--chlorohexadienone (4-CD) precipitate on the electrode, leading to a significant decrease of photocurrent signal. The decreased photocurrent correlates linearly with the target concentration from 0.1 fM to 1 nM with a detection limit of 66.2 aM (S/N = 3). The proposed PEC strategy exhibits delightful selectivity, reproducibility and stability.

Ligand Regulation Strategy to Modulate ROS Nature in a Rhodamine-Iridium(III) Hybrid System for Phototherapy.

The efficacy of photodynamic therapy (PDT) is highly dependent on the photosensitizer features. The reactive oxygen species (ROS) generated by photosensitizers is proven to be associated with immunotherapy by triggering immunogenic cell death (ICD) as well. In this work, we establish a rhodamine-iridium(III) hybrid model functioning as a photosensitizer to comprehensively understand its performance and potential applications in photodynamic immunotherapy. Especially, the correlation between the ROS generation efficiency and the energy level of the Ir(III)-based excited state (T1'), modulated by the cyclometalating (C∧N) ligand, is systematically investigated and correlated. We prove that in addition to the direct population of the rhodamine triplet state (T1) formed through the intersystem crossing process with the assistance of a heavy Ir(III) metal center, the fine-tuned T1' state could act as a relay to provide an additional pathway for promoting the cascade energy transfer process that leads to enhanced ROS generation ability. Moreover, type I ROS can be effectively produced by introducing sulfur-containing thiophene units in C∧N ligands, providing a stronger M1 macrophage-activation efficiency under hypoxia to evoke in vivo antitumor immunity. Overall, our work provides a fundamental guideline for the molecular design and exploration of advanced transition-metal-based photosensitizers for biomedical applications.

Three new red neutral and ionic iridium(III) complexes based on the same main ligand and auxiliary ligand but with different counterions for solution-processed organic light-emitting diodes.

Three new neutral and ionic phosphorescent iridium(III) complexes were successfully prepared using 1-(6-methoxynaphthalen-2-yl)isoquinoline as the main ligand, while the auxiliary ligand was 2-(2-1H-imidazolyl)pyridine. Three complexes (Ir1, Ir2, Ir3) showed red emission, peaking at 610, 609, and 615 nm, respectively, and they exhibited good solubility and excellent photophysical properties in different solvents, which is suitable to prepare organic light-emitting diodes (OLEDs) by solution method. Among the three OLEDs prepared by iridium(III) complexes using the solution method, the device based on Ir2 possessed better electroluminescent properties, and its maximum brightness, current efficiency (CE), power efficiency (PE), and the maximum external quantum efficiency (EQE) were 507.2 cd m-2 , 0.14 cd A-1 , 0.06 lm W-1 , and 0.14%. respectively, proving that the three complexes have a certain of potential for OLEDs applications and are expected to expand the applications of iridium(III) complexes for OLEDs.

Lactic acid responsive sequential production of hydrogen peroxide and consumption of glutathione for enhanced ferroptosis tumor therapy.

Ferroptosis is characterized by the lethal accumulation of lipid reactive oxygen species (ROS), which has great potential for tumor therapy. However, developing new ferroptosis-inducing strategies by combining nanomaterials with small molecule inducers is important. In this study, an enzyme-gated biodegradable natural-product delivery system based on lactate oxidase (LOD)-gated biodegradable iridium (Ir)-doped hollow mesoporous organosilica nanoparticles (HMONs) loaded with honokiol (HNK) (HNK@Ir-HMONs-LOD, HIHL) is designed to enhance ferroptosis in colon tumor therapy. After reaching the tumor microenvironment, the outer LOD dissociates and releases the HNK to induce ferroptosis. Moreover, the released dopant Ir4+ and disulfide-bridged organosilica frameworks deplete intracellular glutathione (GSH), which is followed by GSH-mediated Ir(IV)/Ir(III) conversion. This leads to the repression of glutathione peroxidase 4 (GPX4) activity and decomposition of intratumoral hydrogen peroxide (H2O2) into hydroxyl radicals (•OH) by Ir3+-mediated Fenton-like reactions. Moreover, LOD efficiently depletes lactic acid to facilitate the generation of H2O2 and boost the Fenton reaction, which in turn enhances ROS generation. With the synergistic effects of these cascade reactions and the release of HNK, notable ferroptosis efficacy was observed both in vitro and in vivo. This combination of natural product-induced and lactic acid-responsive sequential production of H2O2 as well as the consumption of glutathione may provide a new paradigm for achieving effective ferroptosis-based cancer therapy.

Synthesis and mitochondria-localized iridium (III) complexes induce cell death through pyroptosis and ferroptosis pathways.

This paper introduces a new ligand, 4,6-dichloro-5-(1H-imidazo [4,5-f]phenanthroline-2-yl)pyrimidin-2-amine (DPPA), and its corresponding new iridium(III) complexes: [Ir(ppy)2(DPPA)](PF6) (2a) (where ppy represents deprotonated 2-phenylpyridine), [Ir(bzq)2(DPPA)](PF6) (2b) (with bzq indicating deprotonated benzo[h]quinoline), and [Ir(piq)2(DPPA)](PF6) (2c) (piq denoting deprotonated 1-phenylisoquinoline). The cytotoxic effects of both DPPA and 2a, 2b, and 2c were evaluated against human lung carcinoma A549, melanoma B16, colorectal cancer HCT116, human hepatocellular carcinoma HepG2 cancer cell lines, as well as the non-cancerous LO2 cell line using the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. While DPPA exhibited moderate anticancer activity toward A549, B16, HCT116 and HepG2 cells, complexes 2a, 2b, and 2c displayed remarkable efficacy against A549, B16, and HCT116 cells. The cell colonies and wound healing were investigated. Moreover, various aspects of the anticancer mechanisms were explored. The cell cycle analyses revealed that the complexes block cell proliferation of A549 cells during the S phase. Complex 2c induce an early apoptosis, while 2a and 2b cause a late apoptosis. The interaction of 2a, 2b and 2c with endoplasmic reticulum and mitochondria was identified, leading to elevated ROS and Ca2+ amounts. This resulted in a reduced mitochondrial membrane potential, mitochondrial permeability transition pore opening, and an increase of cytochrome c. Also, ferroptosis was investigated through measurements of intracellular glutathione (GSH), malondialdehyde (MDA), and recombinant glutathione peroxidase (GPX4) protein expression. The pyroptosis was explored via cell morphology, release of lactate dehydrogenase (LDH) and expression of pyroptosis-related proteins. RNA sequencing was applied to examine the signaling pathways. Western blot analyses illuminated that the complexes regulate the expression of Bcl-2 family proteins. Additionally, an in vivo antitumor study demonstrated that complex 2c exhibited a remarkable inhibitory rate of 58.58% in restraining tumor growth. In summary, the findings collectively suggest that the iridium(III) complexes induce cell death via ferroptosis, apoptosis by a ROS-mediated mitochondrial dysfunction pathway and GSDMD-mediated pyroptosis.

Systematic review on antibacterial photodynamic therapeutic effects of transition metals ruthenium and iridium complexes.

The prevalence of antibiotic-resistant pathogenic bacteria poses a significant threat to public health and ranks among the principal causes of morbidity and mortality worldwide. Antimicrobial photodynamic therapy is an emerging therapeutic technique that has excellent potential to embark upon antibiotic resistance problems. The efficacy of this therapy hinges on the careful selection of suitable photosensitizers (PSs). Transition metal complexes, such as Ruthenium (Ru) and Iridium (Ir), are highly suitable for use as PSs because of their surface plasmonic resonance, crystal structure, optical characteristics, and photonics. These metals belong to the platinum family and exhibit similar chemical behavior due to their partially filled d-shells. Ruthenium and Iridium-based complexes generate reactive oxygen species (ROS), which interact with proteins and DNA to induce cell death. As photodynamic therapeutic agents, these complexes have been widely studied for their efficacy against cancer cells, but their potential for antibacterial activity remains largely unexplored. Our study focuses on exploring the antibacterial photodynamic effect of Ruthenium and Iridium-based complexes against both Gram-positive and Gram-negative bacteria. We aim to provide a comprehensive overview of various types of research in this area, including the structures, synthesis methods, and antibacterial photodynamic applications of these complexes. Our findings will provide valuable insights into the design, development, and modification of PSs to enhance their photodynamic therapeutic effect on bacteria, along with a clear understanding of their mechanism of action.

A Ferroptosis-Inducing Arsenene-Iridium Nanoplatform for Synergistic Immunotherapy in Pancreatic Cancer.

Due to multidrug resistance and the high risk of recurrence, effective and less toxic alternative pancreatic cancer treatments are urgently needed. Pancreatic cancer cells are highly resistant to apoptosis but sensitive to ferroptosis. In this study, an innovative nanoplatform (AsIr@PDA) was developed by electrostatic adsorption of a cationic iridium complex (IrFN) onto two-dimensional (2D) arsenene nanosheets. This nanoplatform exhibits superior ferroptosis-inducing effects with high drug loading capacity and, importantly, excellent anti-cancer immune activation function, leading to efficient elimination of pancreatic tumors with no observable side effects. Interestingly, AsIr@PDA significantly prevents the recurrence of pancreatic cancer in vivo when compared with a cisplatin-loaded nanoplatform. This designed nanoplatform demonstrated superior therapeutic efficacy by synergistic ferroptosis-induced chemotherapy with immunotherapy via an all-in-one strategy, providing new insights for future pancreatic cancer therapy.

Iridium nanoparticles supported on polyaniline nanotubes for peroxidase mimicking towards total antioxidant capacity assay of fruits and vegetables.

In this study, a straightforward approach is presented for the first time to anchor Ir nanoparticles on the surface of uniform polyaniline (PANi) nanotubes (NTs), which can be used as an efficient peroxidase (POD)-like catalyst. The morphology and chemical structure of the PANi-Ir nanocomposite are characterized by scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), X-ray diffractometer (XRD), Raman and X-ray photoelectron spectroscopy (XPS) measurements. Owing to the strong interaction between Ir nanoparticles and PANi, a remarkable catalytic enhancement is achieved compared to the bare Ir black catalyst and individual PANi NTs, dominating withan electron transfer mechanism. Furthermore, an efficient colorimetric sensor for ascorbic acid (AA) is developed with a low detection limit of 1.0 µM (S/N = 3), and a total antioxidant capacity (TAC) sensing platform is also constructed for the rigorous detection and analysis of fruits and vegetables.

Photoactivatable, mitochondria targeting dppz iridium(III) complex selectively interacts and damages mitochondrial DNA in cancer cells.

Cyclometalated Ir(III) complex [Ir(L)2(dppz)]PF6 (where L = 1-methyl-2-(thiophen-2-yl)-1H-benzo[d]imidazole and dppz = dipyrido [3,2-a:2',3'-c]phenazine) (Ir1) is potent anticancer agent whose potency can be significantly increased by irradiation with blue light. Structural features of the cyclometalated Ir(III) complex Ir1 investigated in this work, particularly the presence of dppz ligand possessing an extended planar area, suggest that this complex could interact with DNA. Here, we have shown that Ir1 accumulates predominantly in mitochondria of cancer cells where effectively and selectively binds mitochondrial (mt)DNA. Additionally, the results demonstrated that Ir1 effectively suppresses transcription of mitochondria-encoded genes, especially after irradiation, which may further affect mitochondrial (and thus also cellular) functions. The observation that Ir1 binds selectively to mtDNA implies that the mechanism of its biological activity in cancer cells may also be connected with its interaction and damage to mtDNA. Further investigations revealed that Ir1 tightly binds DNA in a cell-free environment, with sequence preference for GC over AT base pairs. Although the dppz ligand itself or as a ligand in structurally similar DNA-intercalating Ru polypyridine complexes based on dppz ligand intercalates into DNA, the DNA binding mode of Ir1 comprises surprisingly a groove binding rather than an intercalation. Also interestingly, after irradiation with visible (blue) light, Ir1 was capable of cleaving DNA, likely due to the production of superoxide anion radical. The results of this study show that mtDNA damage by Ir1 plays a significant role in its mechanism of antitumor efficacy. In addition, the results of this work are consistent with the hypothesis and support the view that targeting the mitochondrial genome is an effective strategy for anticancer (photo)therapy and that the class of photoactivatable dipyridophenazine Ir(III) compounds may represent prospective substances suitable for further testing.

A Semi-Automated, High-Throughput Approach for the Synthesis and Identification of Highly Photo-Cytotoxic Iridium Complexes.

The discovery of new compounds with pharmacological properties is usually a lengthy, laborious and expensive process. Thus, there is increasing interest in developing workflows that allow for the rapid synthesis and evaluation of libraries of compounds with the aim of identifying leads for further drug development. Herein, we apply combinatorial synthesis to build a library of 90 iridium(III) complexes (81 of which are new) over two synthesise-and-test cycles, with the aim of identifying potential agents for photodynamic therapy. We demonstrate the power of this approach by identifying highly active complexes that are well-tolerated in the dark but display very low nM phototoxicity against cancer cells. To build a detailed structure-activity relationship for this class of compounds we have used density functional theory (DFT) calculations to determine some key electronic parameters and study correlations with the experimental data. Finally, we present an optimised semi-automated synthesise-and-test protocol to obtain multiplex data within 72 hours.

Ir(III) Half-Sandwich Photosensitizers with a π-Expansive Ligand for Efficient Anticancer Photodynamic Therapy.

One approach to reduce the side effects of chemotherapy in cancer treatment is photodynamic therapy (PDT), which allows spatiotemporal control of the cytotoxicity. We have used the strategy of coordinating π-expansive ligands to increase the excited state lifetimes of Ir(III) half-sandwich complexes in order to facilitate the generation of 1O2. We have obtained derivatives of formulas [Cp*Ir(C∧N)Cl] and [Cp*Ir(C∧N)L]BF4 with different degrees of π-expansion in the C∧N ligands. Complexes with the more π-expansive ligand are very effective photosensitizers with phototoxic indexes PI > 2000. Furthermore, PI values of 63 were achieved with red light. Time-dependent density functional theory (TD-DFT) calculations nicely explain the effect of the π-expansion. The complexes produce reactive oxygen species (ROS) at the cellular level, causing mitochondrial membrane depolarization, cleavage of DNA, nicotinamide adenine dinucleotide (NADH) oxidation, as well as lysosomal damage. Consequently, cell death by apoptosis and secondary necrosis is activated. Thus, we describe the first class of half-sandwich iridium cyclometalated complexes active in PDT.

Phototoxicity of cyclometallated Ir(III) complexes bearing a thio-bis-benzimidazole ligand, and its monodentate analogue, as potential PDT photosensitisers in cancer cell killing.

Two novel cyclometallated iridium(III) complexes have been prepared with one bidentate or two monodentate imidazole-based ligands, 1 and 2, respectively. The complexes showed intense emission with long lifetimes of the excited state. Femtosecond transient absorption experiments established the nature of the lowest excited state as 3IL state. Singlet oxygen generation with good yields (40% for 1 and 82% for 2) was established by detecting 1O2 directly, through its emission at 1270 nm. Photostability studies were also performed to assess the viability of the complexes as photosensitizers (PS) for photodynamic therapy (PDT). Complex 1 was selected as a good candidate to investigate light-activated killing of cells, whilst complex 2 was found to be toxic in the dark and unstable under light. Complex 1 demonstrated high phototoxicity indexes (PI) in the visible region, PI > 250 after irradiation at 405 nm and PI > 150 at 455 nm, in EJ bladder cancer cells.

Site-Specific Anchoring a Luminescent Tag in a Protein with Non-Emissive Iridium(III) Complex.

Site-specific modification of proteins with synthetic fluorescent tag effectively improves the resolution of imaging, and such a labeling method with negligible three-dimensional structural perturbations and minimal impact on the biological functions of proteins is of high interest to dissect the high-resolution activities of biomolecules in complex systems. To this end, several non-emissive iridium(III) complexes [Ir(C-N)2 (H2 O)2 ]+ OTF- (C-N denotes various cyclometalated ligands) were designed and synthesized. These complexes were tested for attaching a protein by coordinating to H/X (HisMet, HisHis, and HisCys) that are separated by i and i+4 in α-helix. Replacement of the two labile water ligands in the iridium(III) complex by a protein HisHis pair increases the luminescent intensity up to over 100 folds. This labeling approach has been demonstrated in a highly specific and efficient manner in a number of proteins, and it is also feasible for labeling target proteins in cell lysates.

Mitochondria-targeted iridium(III) complexes encapsulated in liposome induce cell death through ferroptosis and gasdermin-mediated pyroptosis.

This paper unveils a novel perspective on synthesis and characterization of the ligand 5-bromo-2-amino-2'-(phenyl-1H-imidazo[4,5-f][1,10]phenanthroline) (BAPIP), and its iridium(III) complexes [Ir(PPY-)2(BAPIP)](PF6) (1a, with PPY- as deprotonated 2-phenylpyridine), [Ir(PIQ-)2(BAPIP)](PF6) (1b, piq- denoting deprotonated 1-phenylisoquinoline), and [Ir(BZQ-)2(BAPIP)](PF6) (1c, bzq- signifying deprotonated benzo[h]quinoline). Systematic evaluation of the cytotoxicity of 1a, 1b, and 1c across diverse cell lines encompassing B16, HCT116, HepG2, A549, HeLa, and LO2 using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Unexpectedly, compounds 1b and 1c demonstrated no cytotoxicity against the above cell lines. Motivated by the pursuit of heightened anti-proliferative potential, a strategic encapsulation approach yielded liposomes 1alip, 1blip, and 1clip. As expectation, 1alip, 1blip, and 1clip displayed remarkable anti-proliferative efficacy, particularly noteworthy in A549 cells, exhibiting IC50 values of 4.9 ± 1.0, 5.9 ± 0.1, and 7.6 ± 0.2 µM, respectively. Moreover, our investigation illuminated the mitochondrial accumulation of these liposomal entities, 1alip, 1blip, and 1clip, evoking apoptosis through the mitochondrial dysfunction mediated by reactive oxygen species (ROS). The ferroptosis was confirmed by decrease in glutathione (GSH) concentrations, the downregulation of glutathione peroxidase 4 (GPX4), increase of high mobility group protein 1 (HMGB1), and lipid peroxidation. Simultaneously, pyroptosis as another mode of cell death was undertaken. RNA-sequencing was employed to investigate intricate signalling pathways. In vivo examination provided tangible evidence of 1alip in effectively curbing tumor growth. Collectively, this study provides a multifaceted mode of cellular demise orchestrated by 1a, 1alip, 1blip, and 1clip, involving pathways encompassing apoptosis, ferroptosis, and pyroptosis.