Liposomal Nanoparticles Research Articles

Manufacturing of Liposomes Using a Stainless-Steel Microfluidic Device: An Investigation into Design of Experiments.

Liposomes are highly beneficial nanocarrier systems due to their biocompatibility, low toxicity, and exceptional inclusiveness, which lead to improved drug bioavailability. For biological applications, accurate control over these nanoparticles' mean size and size distribution is essential. Micromixers facilitate the continuous production of liposomes, enhancing the precision of size regulation and reproducibility. In this research, the performance of a stainless steel 316L micromixer was evaluated by using COMSOL Multiphysics simulations. The liposomes were precisely optimized using design of experiments techniques in a microfluidic setup, and then dexamethasone sodium phosphate (DSP) was successfully encapsulated in liposome nanoparticles. The physicochemical characteristics of liposomes, such as their ζ-potential, size, DSP loading capacity, encapsulation efficiency, and drug release, were assessed. Transmission electron microscopy and dynamic light scattering analysis were used to examine the structures of the liposomes. The drug release kinetics study was conducted to analyze the drug delivery system, and the Higuchi equation was determined to be the most suitable equation. The microfluidic chip was shown to be capable of creating small-sized liposomes with a size as small as 130 nm, exhibiting monodispersed characteristics and low polydispersity liposome populations.

Advanced Targeted Therapy for Colorectal Cancer with Lipid Nanoparticles.

Targeted therapy for colorectal cancer (CRC) appears to have great potential with lipid nanoparticles (LNPs). The advances in LNP-based techniques, such as liposomes, exosomes, micelles, solid lipid nanoparticles (SLNs), nano-cubosomes, and plant- derived LNPs (PDLNPs), are explored in detail in this thorough review. Every platform provides distinct advantages: liposomes enable precise drug release and improved delivery; exosomes function as organic nanocarriers for focused treatment; SLNs offer greater stability; micelles enhance drug solubility and resistance; nano-cubosomes tackle low bioavailability; and PDLNPs offer biocompatible substitutes. The mechanisms, benefits, drawbacks, and therapeutic potential of these LNP platforms in the treatment of colorectal cancer are highlighted in the review. The review highlights how crucial it is to use these technologies for efficient CRC management and looks at potential future developments for them. The controlled release properties of liposomes and solid liposome nanoparticles (SLNs) improve the stability and bioavailability of medicinal compounds. On the other hand, exosomes and micelles provide answers for medication resistance and solubility issues, respectively. Novel strategies for resolving bioavailability problems and enhancing biocompatibility include nano-cubosomes and PDLNPs. These LNP-based systems are promising in clinical applications for boosting therapeutic efficacy, decreasing systemic toxicity, and facilitating tailored drug delivery. By incorporating these nanotechnologies into CRC treatment plans, present therapeutic approaches may be completely changed, and more individualized and efficient treatment choices may be provided. To completely comprehend the advantages and drawbacks of these LNP systems in therapeutic settings, as well as to and optimize them, more study is recommended by the review. Treatment for colorectal cancer may be much improved in the future thanks to developments in LNP-based drug delivery systems. These technologies hold great promise for improving patient outcomes and advancing the field of oncology by tackling important issues related to medication delivery and bioavailability.

Doxorubicin prodrug for γ-glutamyl transpeptidase imaging and on-demand cancer therapy.

The γ-glutamyl transpeptidase (γ-GGT) is an important tumor marker, which has been reported to be firmly associated with the developmental stage of liver cancer. Therefore, it makes sense to image and monitor γ-GGT level and design γ-GGT-responsive prodrug for integrated diagnosis and treatment of liver cancer. Herein, we prepare a doxorubicin (Dox) prodrug for imaging γ-GGT and on-demand treating liver cancer. When γ-GGT exists, the γ-glutamyl group will be cut off to liberate free Dox for monitoring cancer progression and killing tumor cells. Fortunately, little Dox is released due to the low level of γ-GGT in normal cells, which improves the safety and efficiency of chemotherapy. To further improve the tumor targeted ability, Dox prodrug is loaded in hyaluronic acid modified liposome nanoparticles to form the nano-prodrug. Then nano-prodrug is enriched in the tumor by binding to the high expressed CD44 on cancer cells. With the assistance of anti-PD-L1, nano-prodrug effectively inhibits the growth of proximal and distal tumors.

Bright NIR-II emissive cyanine dye-loaded lipoprotein-mimicking nanoparticles for fluorescence imaging-guided and targeted NIR-II photothermal therapy of subcutaneous glioblastoma

Cyanine dye-containing nanoparticles have widely been used in “all-in-one” NIR fluorescence imaging (FI)-guided photothermal therapy (PTT) because of their intrinsically large extinction coefficient and available physical and chemical modulation methods to tune absorption and emission wavelengths. The combination of good brightness and excellent tumor-targeting capacity is the key to realize efficient NIR-II FI-guided PTT. In this study, by covalently decorating NIR-II absorptive cyanine dyes with bulky AIE motify, we demonstrate how steric hindrance suppresses π-π stacking-induced fluorescence quenching and contributes to the good brightness of NIR-II FI of subcutaneous glioblastoma. The resulting cyanine dye (C12-TPAE) is 5 times brighter than the original cyanine dye in the formulated liposomal nanoparticles and C12-TPAE-AL has a high photothermal conversion efficiency of 62.4%, with good colloidal and light stability. Importantly, the ApoE peptide is absorbed on the liposomal surface, yielding lipoprotein-mimicking nanoparticles, which achieve active targeting of glioblastoma and efficient FI-guided PTT without tumor recurrence without any side effects on normal organs (heart, kidneys, liver, spleen, or lung). This research highlights a facile design route for bright NIR-II emissive and NIR-II photothermal cyanine dyes and indicates that cyanine dye-containing biomimetic theranostic nanoplatforms are promising candidates for future precision therapy.

Biomimetic niosomal versus liposomal nanoparticle-based aspirin injection for treating stroke and myocardial infarction.

In this work, we are comparing biomimetic niosomal nanoparticles (BNNs) with biomimetic liposomal nanoparticles (BLNs) and studying their drug carrier properties. A-BNNs and A-BLNs are prepared by lipid hydration method and characterized using DLS for size and zeta potential analysis, surface morphology by SEM, structural details by TEM, crystallinity and phase change by XRD, thermodynamic properties by DSC, TGA and DTGA, drug carrier properties by entrapment efficiency, drug release studies by open-end tube method and its mechanistic assessment by fitting with various models such as zero order, first order, Higuchi and Korsmeyer-Peppas models. The A-BNNs had an average size of 157.0 ± 3.58nm and A-BLNs had an average size of 173 ± 1.24nm. The A-BNNs had an average zeta potential of -29.0 ± 1.11mV and A-BLNs had an average zeta potential of -46.5 ± 1.11mV. The A-BNNs have an average entrapment efficiency of 94 ± 0.4% and A-BLNs have an average entrapment efficiency of 98 ± 0.14%. The BNNs have an average drug release of 78.12 ± 1.57% and A-BLNs have an average release of 98.41 ± 1.87% over 24hours. Our results show that the vesicular size dependence influences the resulting nanoparticle drug carrier properties. This is a robust demonstration of the phenomena at the nanoscale that the precursor vesicular system size dependency will be reflected in bulk-engineered nanoparticle properties. These novel nanoparticles are potential candidates for development as an injection to suppress clots in stroke and myocardial infarction.

Synthesis and Characterization of Transferrin and Cell-Penetrating Peptide-Functionalized Liposomal Nanoparticles to Deliver Plasmid ApoE2 In Vitro and In Vivo in Mice.

Alzheimer's disease (AD) is a prevalent neurodegenerative condition characterized by the aggregation of amyloid-β plaques and neurofibrillary tangles in the brain, leading to synaptic dysfunction and neuronal degeneration. Recently, new treatment approaches involving drugs such as donanemab and lecanemab have been introduced for AD. However, these drug regimens have been associated with adverse effects, leading to the exploration of gene therapy as a potential treatment option. The apolipoprotein E (ApoE) isoforms (ApoE2, ApoE3, and ApoE4) play pivotal roles in AD pathology, with ApoE2 known for its protective effects against AD, making it a promising candidate for gene therapy interventions. However, delivering therapeutics across the blood-brain barrier (BBB) remains a crucial challenge in treating neurological disorders. Liposomes, lipid-based vesicles, are effective nanocarriers due to their ability to shield therapeutics from degradation, though they often lack specificity for brain delivery. To address this issue, liposomes were functionalized with cell-penetrating peptides such as penetratin (Pen), cingulin (Cgn), and a targeting ligand transferrin (Tf). This modification strategy aimed to enhance the delivery of therapeutic ApoE2 plasmids across the BBB to neurons, thereby increasing the level of ApoE2 protein expression. Experimental findings demonstrated that dual-functionalized liposomes (CgnTf and PenTf) exhibited higher cellular uptake, biodistribution, and transfection efficiency than single-functionalized (Pen, Cgn, or Tf) and nonfunctionalized liposomes. In vitro studies using primary neuronal cells, bEnd.3 cells, and primary astrocytes consistently supported these findings. Following a single dose treatment via tail vein administration in C57BL6/J mice, in vivo biodistribution results showed significantly higher biodistribution levels in the brain (∼12% ID/gram of tissue) for dual-functionalized liposomes. Notably, treatment with dual-functionalized liposomes resulted in a 2-fold increase in ApoE2 expression levels compared to baseline levels. These findings highlight the potential of dual-functionalized liposomes as an efficacious delivery system for ApoE2 gene therapy in AD, highlighting a promising strategy to address the disease's underlying mechanisms.

Application of liposomal nanoparticles of berberine in photodynamic therapy of A549 lung cancer spheroids

Application of liposomes is a critical strategy in drug delivery and increase cellular uptake of drugs having low water solubility. Berberine (BBR) is a bioactive compound found in several plants, including Goldenseal, Barberry, and Oregon grape. It has garnered attention for its various health benefits, particularly in metabolic health and antimicrobial activity. However, one of the challenges associated with BBR is its water solubility. Moreover, BBR has photosensitizing potential via absorbance of light and generation of free radicals. Hence, to improve water solubility and bioavailability, one of the important strategies employed is using lipid-based carriers to enhance solubility. In this study we employed liposomes to deliver BBR in A549 lung cancer spheroid cells to enhance photodynamic therapy efficacies. Results from the EDS and UV–Vis spectroscopy revealed that the BBR had been loaded onto liposomes, with three peaks appearing between 250 and 450 nm. Morphology of Lipo@BBR nanocomplex was in wavy crest shape and the size was 56.99 ± 3.74 nm in SEM and TEM analysis, respectively. FTIR data illustrated that Lipo@BBR has four significant peaks at 1250, 1459, 1736, and 2907 cm−1. DLS data showed that Lipo@BBR has a negative surface charge with a −10.7 Zeta Potential (mV). Additionally, based on Zetasizer measurements, the size of Lipo@BBR complex was 82.7 ± 6.5. Cytotoxicity assay investigation with MTT assay presented that IC50 of Lipo@BBR in PDT was 10 ± 0.5 μg/mL that led to a volume reduction of the A549 spheroids after five sessions of PDT fractionation (total light dose was set at 25 J/cm2). qPCR and immunofluorescence results demonstrated that Lipo@BBR increases the BAX/BCL2 ratio in A549 spheroid cells, hence improving PDT efficiency. In conclusion, our results illustrated that safe dose of Lipo@BBR (10 ± 0.5 μg/mL) in PDT fractionation protocol can be one of the strategies to suppress the tumor volume and cell death proliferation. Authors recommend using Lipo@BBR nanocomplex in PDT fractionation as well as more in vivo investigation is warranted.

Synthesis of liposomal nanoparticles to load 4-farnesyloxycoumarin and investigating its anti-cancer and anti-metastatic effects

The aim of this study was to load 4-farnesyloxycoumarin (4-FLC) in nanoliposomes (4-FLC-LNPs) and evaluate its anti-cancer and anti-metastatic effects. 4-FLC-LNPs were synthesized using a combination of lecithin-cholesterol-polyethylene glycol. The physicochemical properties were evaluated using DLS, FTIR, and microscopy methods. The toxicity against breast cancer (MCF-7), prostate cancer (PS3), pancreatic cancer (PANC), gastric cancer (AGS), and normal cell lines (HUVEC) was evaluated using the MTT assay. Fluorescent staining and flow cytometry were used to assess the occurrence of apoptosis. Molecular analysis methods were used to study the apoptosis and metastasis effects of these nanoliposomes. The antioxidant power of 4-FLC-LNPs was measured using the ABTS and DPPH free radicals methods. 4-FLC-LNPs exhibit a spherical morphology, with an average size of 57.43 nm, a polydispersity index of 0.29, and a zeta potential of −31.4 mV. They demonstrate an encapsulation efficiency of 82.4% for 4-FLC. The IC50 value of 4-FLC-LNPs against the breast cancer cell line was reported as the most sensitive, at approximately 60 μg/mL. ABTS and DPPH results were reported at approximately 30 µg/mL. The inductive effects of nanoliposomes on the apoptosis process were confirmed by an increase in the number of apoptotic cells, as well as the arrest of cells in various phases of cell growth. The increased expression of BAX and decreased expression of Bcl-2, MMP-2, and MMP-9 confirmed the pro-apoptotic and anti-metastatic effects of 4-FLC-LNPs. These finding validate the therapeutic potential of 4-FLC-LNPs, which may be utilized in preclinical studies.

Abstract IA007: Modulating cfDNA biology to enhance liquid biopsies

Abstract Liquid biopsies could transform cancer care but require higher sensitivity to detect early-stage tumors and minimal residual disease (MRD) and to enable tumor molecular profiling and therapy response monitoring for most patients. In this talk, I will focus on the significant biological bottlenecks upstream of cell-free DNA (cfDNA) testing. I will posit that in many circumstances, insufficient circulating tumor DNA (ctDNA) drawn in a blood tube cannot be overcome by assay technology alone, and that in vivo modulation of cfDNA biology may also be required to enhance liquid biopsies. Inspired by widespread use of diagnostic drugs in other areas of medicine, we sought to create the first “priming agents” for liquid biopsies that could be administered before a blood draw to recover more ctDNA. I will describe two such approaches—a monoclonal antibody against double-stranded DNA and a liposome nanoparticle—that briefly attenuate cfDNA clearance by shielding it from nuclease digestion and cellular uptake. These enabled >10x more ctDNA to be collected when administered within 1-2 hours of a blood draw in mice. This improved the analytical limit of detection for ctDNA testing by >10-fold, provided more complete representation of the tumor genome in each blood sample, and increased the sensitivity for detection of small tumors from <10% to >75% in mice. Envisioning a future where liquid biopsies are optionally enhanced with priming, I will also explore a unique potential pairing with our tumor-informed, whole-genome, mutation enrichment sequencing MRD test called MAESTRO, and how it stands to enable routine ctDNA detection below 1 part per million. Citation Format: Viktor Adalsteinsson. Modulating cfDNA biology to enhance liquid biopsies [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr IA007.

Preparation and Characterization of Ozonated Liposomes Loaded with Curcumin: A Potential Approach for Diabetic Retinopathy Treatment

Background: Limitations in drug penetration are overcome by nanotechnology, particularly liposomes, which enhance targeted administration of ocular medications. Liposomes can augment the therapeutic effects of curcumin, a natural compound with positive impacts on the retina. Treatments for eye diseases can also benefit from the antibacterial properties of ozonated oil liposomes. Objectives: This study aims to develop and evaluate ozonated liposomes loaded with curcumin for ocular drug delivery applications, specifically targeting diabetic retinopathy (DR). Methods: Liposomal nanoparticles were prepared using thin-film hydration, incorporating phospholipids, lecithin, cholesterol, ozonated oil, and curcumin. We assessed physicochemical properties including particle size, zeta potential, encapsulation efficiency (EE), and morphology. Drug release profiles and stability studies were also conducted. Results: The optimized liposomes showed a particle size of 84.77 nm, a zeta potential of -16.8 mV, and an EE of 94.73%. The formulation exhibited sustained curcumin release over 24 hours, reaching 82.09% cumulative release. Stability studies indicated minimal changes in key parameters over three months at room temperature. Conclusions: The developed ozonated liposomal formulation demonstrates promising characteristics for curcumin delivery, potentially enhancing its therapeutic efficacy in ocular applications, particularly for DR.

Targeted Delivery of Celastrol by GA-Modified Liposomal Calcium Carbonate Nanoparticles to Enhance Antitumor Efficacy Against Breast Cancer.

Breast cancer, a leading health threat affecting millions worldwide, requires effective therapeutic interventions. Celastrol (CEL), despite its antitumor potential, is limited by poor solubility and stability. This study aimed to enhance CEL's efficacy by encapsulating it within glycyrrhizic acid (GA)-modified lipid calcium carbonate (LCC) nanoparticles for targeted breast cancer therapy. The 4T1 mouse breast cancer cells were used for the study. GA-LCC-CEL nanoparticles were prepared using a gas diffusion method and a thin-film dispersion method. GA-LCC-CEL were characterized using the zeta-potential, dynamic light scattering and transmission electron microscope (TEM). The in vitro release behavior of nanoparticles was assessed using the in vitro dialysis diffusion method. Cellular uptake was examined using flow cytometry and confocal microscopy. Intracellular ROS and Rhodamine 123 levels were observed under fluorescence microscopy. MTT and colony formation assays assessed cytotoxicity and proliferation, and apoptosis was analyzed by Annexin V-FITC/PI staining. Wound healing and transwell assays evaluated migration, and Western blotting confirmed protein expression changes related to apoptosis and migration. GA-LCC-CEL nanoparticles displayed a well-defined core-shell structure with a uniform size distribution. They showed enhanced anti-proliferative and pro-apoptotic effects against 4T1 cells and significantly reduced breast cancer cell invasion and migration. Additionally, GA-LCC-CEL modulated epithelial-mesenchymal transition (EMT) protein expression, downregulating Snail and ZEB1, and upregulating E-cadherin. GA-LCC-CEL nanoparticles represent a promising targeted drug delivery approach for breast cancer, enhancing CEL's antitumor efficacy and potentially inhibiting cancer progression by modulating EMT-related proteins.

Targeting Synovial Macrophages with Astaxanthin-Loaded Liposomes for Antioxidant Treatment of Osteoarthritis.

Osteoarthritis (OA) is a chronic joint disease highly associated with an imbalance in the network of inflammatory factors and typically characterized by oxidative stress and cartilage damage. Moreover, the specificity of the joint structure makes it difficult for drugs to achieve good penetration and effective enrichment in the joint cavity. Therefore, therapeutic strategies that increase the specific targeting of drugs to inflammatory joint and incorporate antioxidative stress effects are important to improve the efficacy of OA. Here, we developed a folic acid-modified liposomal nanoparticle (AST@Lip-FA) loaded with the antioxidant astaxanthin (AST) to enhance the water solubility and stability of AST and to target the delivery of AST to the site of OA, leading to a significant improvement in therapeutic efficacy. In vitro experiments demonstrated that, due to the recognition by FA of the receptor folate receptor β on the surface of activated macrophages, the cellular uptake efficiency of AST@Lip-FA was increased. Meanwhile, intracellularly overexpressed inflammatory mediators such as reactive oxygen species and nitric oxide were efficiently removed by AST@Lip-FA. In addition, in the ACLT-induced OA mouse model, AST@Lip-FA was precisely enriched in the inflamed joints and achieved long-term retention, fully utilizing the anti-inflammatory, antioxidant, and cartilage-protecting effects of AST to effectively alleviate the progression of OA. In summary, AST@Lip-FA has an important prospect as a potential and effective therapeutic strategy for OA.

G‐Quadruplex RNA Based PROTAC Enables Targeted Degradation of RNA Binding Protein FMRP for Tumor Immunotherapy

AbstractFragile X mental retardation protein (FMRP), an RNA binding protein (RBP), is aberrantly hyper‐expressed in human tumors and plays an essential role in tumor invasion, metastasis and immune evasion. However, there is no small‐molecule inhibitor for FMRP so far. In this study, we developed the first FMRP‐targeting degrader based on PROteolysis TArgeting Chimera (PROTAC) technology and constructed a heterobifunctional PROTAC through linking a FMRP‐targeting G‐quadruplex RNA (sc1) to a von Hippel‐Lindau (VHL)‐targeting ligand peptide (named as sc1‐VHLL). Sc1‐VHLL specifically degraded endogenous FMRP via ubiquitination pathway in both mouse and human cancer cells. The FMRP degradation significantly changed the secretion pattern of cancer cells, resulting in higher expression of pro‐inflammatory cytokine and smaller amounts of immunomodulatory contents. Furthermore, sc1‐VHLL, when encapsulated into ionizable liposome nanoparticles (LNP), efficiently targeted tumor site and degraded FMRP in cancer cells. In CT26 tumor‐bearing mouse model, FMRP degradation within tumors substantially promoted the infiltration of lymphocytes and CD8 T cells and reduced the proportion of Treg cells, reshaping the proinflammatory tumor microenvironment and accordingly transforming cold tumor into hot tumor. When combined with immune checkpoint blockade (ICB) therapy, sc1‐VHLL based treatment remarkably inhibited the tumor growth.

G-Quadruplex RNA Based PROTAC Enables Targeted Degradation of RNA Binding Protein FMRP for Tumor Immunotherapy.

Fragile X mental retardation protein (FMRP), an RNA binding protein (RBP), is aberrantly hyper-expressed in human tumors and plays an essential role in tumor invasion, metastasis and immune evasion. However, there is no small-molecule inhibitor for FMRP so far. In this study, we developed the first FMRP-targeting degrader based on PROteolysis TArgeting Chimera (PROTAC) technology and constructed a heterobifunctional PROTAC through linking a FMRP-targeting G-quadruplex RNA (sc1) to a von Hippel-Lindau (VHL)-targeting ligand peptide (named as sc1-VHLL). Sc1-VHLL specifically degraded endogenous FMRP via ubiquitination pathway in both mouse and human cancer cells. The FMRP degradation significantly changed the secretion pattern of cancer cells, resulting in higher expression of pro-inflammatory cytokine and smaller amounts of immunomodulatory contents. Furthermore, sc1-VHLL, when encapsulated into ionizable liposome nanoparticles (LNP), efficiently targeted tumor site and degraded FMRP in cancer cells. In CT26 tumor-bearing mouse model, FMRP degradation within tumors substantially promoted the infiltration of lymphocytes and CD8 T cells and reduced the proportion of Treg cells, reshaping the proinflammatory tumor microenvironment and accordingly transforming cold tumor into hot tumor. When combined with immune checkpoint blockade (ICB) therapy, sc1-VHLL based treatment remarkably inhibited the tumor growth.

A unique and convenient electrochemical biosensor for sodium based on a Na+-pumping rhodopsin

Sodium ion (Na+) detection plays a crucial role in various fields, including clinical diagnostics, environmental monitoring, and food quality control. However, existing techniques often lack sensitivity, selectivity, or practicality. This study presents a novel protein-based electrochemical biosensor for selective and quantitative Na+ detection, utilizing the microbial rhodopsin Nonlabens dokdonensis rhodopsin 2 (NdR2) reconstituted into liposome nanoparticles and immobilized on indium tin oxide (ITO) electrodes. Upon light illumination, the biosensor generates photocurrents proportional to the Na+ concentration in the sample. Extensive characterization unveiled the biosensor’s remarkable selectivity towards Na+ over other cationic species, including K+, Ca2+, Mg2+, and Cs+. Quantitative analysis revealed two linear response ranges: 2–50 mM and 50–200 mM, with a detection limit of 75 μM. The biosensor demonstrated exceptional thermal stability, withstanding 50 °C for 90 min with minimal signal deterioration. Long-term storage stability tests further highlighted its robustness, with consistent Na+ response for up to 17 days. Furthermore, the biosensor successfully detected Na+ in fetal bovine serum, although with a distinct photocurrent profile potentially influenced by interfering components. This pioneering work introduces a highly selective, sensitive, and stable protein-based biosensor for Na+ detection, offering promising implications for diverse applications in clinical diagnostics, environmental monitoring, and quality control, while paving the way for further advancements in biosensing technologies.

MCL1 inhibitor S63845 delivered by follicle-stimulating hormone modified liposome potentiates carboplatin efficacy in ovarian cancer

Platinum resistance cause therapeutic failure and poor prognosis in ovarian cancer, and evasion of apoptosis is a critical factor in chemoresistance. A limited number of FDA-approved anticancer drugs directly target apoptotic pathways. Here, we discovered that MCL1, a critical anti-apoptotic protein, is amplified and associated with platinum resistance and survival in ovarian cancer, assisting in personalized treatment. We further identified S63845 through drug-based screening, the most potent MCL1 inhibitor, which efficiently enhanced carboplatin (CBP) sensitivity in various ovarian cancer models, including primary ovarian cancer cells, orthotopic ovarian cancer, peritoneal metastasis, and human patient-derived xenograft (PDX) models. Mechanistically, S63845 competitively binds to MCL1, disrupts the binding of apoptosis effector (BAK and BAX) or pro-apoptotic BH3 protein (BIM) to MCL1 respectively, and eventually enhances CBP-induced apoptosis.To promote the clinical transformation of S63845, we developed follicle-stimulating hormone-modified liposome nanoparticles (S63845@Lipo-FSH) to enhance stability, membrane penetration, and tumor-targeting capabilities. S63845@Lipo-FSH exhibits a superior therapeutic efficacy and tumor targeting compared to free S63845, even when the dose of S63845 is reduced to one-fifth. Overall, targeting MCL1 by S63845@Lipo-FSH enhances CBP efficiency in ovarian cancer, with safety and efficacy, suggesting that this strategy is effective and promising for clinical application.

A multifunctional targeted nano-delivery system with radiosensitization and immune activation in glioblastoma

Glioblastoma (GBM), the most common primary brain malignancy in adults, is notoriously difficult to treat due to several factors: tendency to be radiation resistant, the presence of the blood brain barrier (BBB) which limits drug delivery and immune-privileged status which hampers effective immune responses. Traditionally, high-dose irradiation (8 Gy) is known to effectively enhance anti-tumor immune responses, but its application is limited by the risk of severe brain damage. Currently, conventional dose segmentation (2 Gy) is the standard radiotherapy method, which does not fully exploit the potential of high-dose irradiation for immune activation. The hypothesis of our study posits that instead of directly applying high doses of radiation, which is risky, a strategy could be developed to harness the immune-stimulating benefits of high-dose irradiation indirectly. This involves using nanoparticles to enhance antigen presentation and immune responses in a safer manner. Angiopep-2 (A2) was proved a satisfactory BBB and brain targeting and Dbait is a small molecule that hijack DNA double strand break damage (DSB) repair proteins to make cancer cells more sensitive to radiation. In view of that, the following two nanoparticles were designed to combine immunity of GBM, radiation resistance and BBB innovatively. One is cationic liposome nanoparticle interacting with Dbait (A2-CL/Dbait NPs) for radiosensitization effect; the other is PLGA-PEG-Mal nanoparticle conjugated with OX40 antibody (A2-PLGA-PEG-Mal/anti-OX40 NPs) for tumor-derived protein antigens capture and optimistic immunoregulatory effect of anti-OX40 (which is known to enhance the activation and proliferation T cells). Both types of nanoparticles showed favorable targeting and low toxicity in experimental models. Specifically, the combination of A2-CL/Dbait NPs and A2-PLGA-PEG-Mal/anti-OX40 NPs led to a significant extension in the survival time and a significant tumor shrinkage of mice with GBM. The study demonstrates that combining these innovative nanoparticles with conventional radiotherapy can effectively address key challenges in GBM treatment. It represents a significant step toward more effective and safer therapeutic options for GBM patients.

Ultrasound-Sensitive Targeted Liposomes as a Gene Delivery System for the Synergistic Treatment of Hepatocellular Carcinoma.

Gene therapy and sonodynamic therapy, as emerging treatment methods, have great potential in cancer treatment. However, there are significant challenges in the in vivo delivery of genes and sonosensitizers during the treatment process, which ultimately affects the therapeutic outcome. In this study, an ultrasound-sensitive targeted liposome nanoparticle system (MLipsiBcl-2) is developed to deliver the sonosensitizers and siRNA for the synergistic treatment of hepatocellular carcinoma. Generation of reactive oxygen species (ROS) by MLipsiBcl-2 can be initiated through ultrasound stimulation, leading to liposome rupture and release of the sonosensitizer and small interfering RNA (siRNA). Furthermore, ROS can disrupt lysosomal membranes, facilitating gene release for downregulating overexpressed antiapoptotic protein levels in cancer cells. Experimental results from in vitro and in vivo studies demonstrated the efficacy of synergistic treatment on hepatocellular carcinoma cells and the high biocompatibility of MLipsiBcl-2 under ultrasound stimulation. The advancement of this ultrasound-sensitive targeted gene delivery system shows potential as a versatile therapeutic platform that is easily operable, presenting a prospect for a synergistic treatment approach across various cancer types.

Cascade piezocatalytic nanoprodrug for synergistic piezocatalytic therapy and sono-activated chemotherapy-augmented immunotherapy

Immune checkpoint blockade (ICB) has shown great promise in the management of various cancers. However, only a small percentage of patients profit from ICB therapy. Immunogenic cell death (ICD) has demonstrated its specific capability in reconstructing the tumor microenvironment (TME) and activating anti-tumor immunity. Herein, an ICD cascade enhancement based on BPTL nanoreactors is proposed to overcome the inadequate damage-associated molecular patterns of ICD inducers. BPTL nanoreactor is formed by incorporating the piezocatalytic BaTiO3 (T-BTO) nanoparticles and paclitaxel (PTX) prodrug that responds to reactive oxygen species (ROS) into liposome nanoparticles for synergistic piezocatalytic and sono-activated chemotherapy (SACT)-augmented immunotherapy. Ultrasound (US) irradiation of the designed BPTL initiates a superior piezodynamic effect and produces ROS by piezocatalytic therapy to trigger ICD. Subsequently, the generated ROS breaks up the thioketal bonds in BPTL, thereby leading to the on-demand release of PTX for SACT and augmented ICD activation. In vivo evaluation demonstrated that BTPL with US irradiation significantly eradicated primary and distant metastatic tumors and markedly prevented the lung metastasis. This nanoplatform combines US-triggered piezocatalytic therapy and SACT for ICD stimulation, providing a robust strategy for amplifying piezocatalytic effect-mediated immune response against tumors.

H2O2-Activatable Liposomal Nanobomb Capable of Generating Hypoxia-Irrelevant Alkyl Radicals by Photo-Triggered Cascade Reaction for High-Performance Elimination of Biofilm Bacteria.

High H2O2 levels are widely present at the infection sites or in the biofilm microenvironment. Herein, hemin with peroxidase-like catalytic activity and its substrate, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), are simultaneously introduced into a liposomal nanoparticle containing thermosensitive 2,2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIBI)-loaded bovine serum albumin (BAG), rationally constructing an H2O2-activatable liposomal nanobomb (Lipo@BHA) for combating biofilm-associated bacterial infections with high performance. In the presence of H2O2, hemin can catalyze the conversion of ABTS into its oxidized form (ABTS·+) with strong near-infrared (NIR) absorption, which produces photonic hyperpyrexia to cause the decomposition of AIBI into oxygen-independent alkyl radicals (·R) and nitrogen (N2) microbubbles. The former not only directly damage bacterial cells but also significantly accelerates the oxidization of ABTS to ABTS·+ for augmenting photothermal-triggered generation of ·R. Interestingly, the released N2 can induce transient cavitation to rupture lysosomal nanoparticle and improve the biofilm permeability, thereby enhancing the antibiofilm effect of Lipo@BHA. The proposed Lipo@BHA exhibits satisfactory multi-mode combination antibacterial properties. Through endogenous H2O2-activated cascade reaction, Lipo@BHA achieves remarkable hypoxia-irrelevant ·R therapy of biofilm-associated wound infections with low cytotoxicity and good in vivo biosafety. Therefore, this work presents a versatile H2O2-activatable cascade ·R generation strategy for biofilm-specific therapeutic applications.