Particle-Based Artificial Antigen-Presenting Cell Systems for T Cell Activation in Adoptive T Cell Therapy.

T cell-based adoptive cell therapy (ACT) has emerged as a promising treatment for various diseases, particularly cancers. Unlike other immunotherapy modalities, ACT involves directly transferring engineered T cells into patients to eradicate diseased cells; hence, it necessitates methods for effectively activating and expanding T cells in vitro. Artificial antigen-presenting cells (aAPCs) have been widely developed based on biomaterials, particularly micro- and nanoparticles, and functionalized with T cell stimulatory antibodies to closely mimic the natural T cell-APC interactions. Due to their vast clinical utility, aAPCs have been employed as an off-the-shelf technology for T cell activation in FDA-approved ACTs, and the development of aAPCs is constantly advancing with the emergence of aAPCs with more sophisticated designs and additional functionalities. Here, we review the recent advancements in particle-based aAPCs for T cell activation in ACTs. Following a brief introduction, we first describe the manufacturing processes of ACT products. Next, the design and synthetic strategies for micro- and nanoparticle-based aAPCs are discussed separately to emphasize their features, advantages, and limitations. Then, the impact of design parameters of aAPCs, such as size, shape, ligand density/mobility, and stiffness, on their functionality and biomedical performance is explored to provide deeper insights into the design concepts and principles for more efficient and safer aAPCs. The review concludes by discussing current challenges and proposing future perspectives for the development of more advanced aAPCs.

Cancer Metastasis-on-a-Chip for Modeling Metastatic Cascade and Drug Screening.

Microfluidic chips are valuable tools for studying intricate cellular and cell-microenvironment interactions. Traditional in vitro cancer models lack accuracy in mimicking the complexities of in vivo tumor microenvironment. However, cancer-metastasis-on-a-chip (CMoC) models combine the advantages of 3D cultures and microfluidic technology, serving as powerful platforms for exploring cancer mechanisms and facilitating drug screening. These chips are able to compartmentalize the metastatic cascade, deepening the understanding of its underlying mechanisms. This article provides an overview of current CMoC models, focusing on distinctive models that simulate invasion, intravasation, circulation, extravasation, and colonization, and their applications in drug screening. Furthermore, challenges faced by CMoC and microfluidic technologies are discussed, while exploring promising future directions in cancer research. The ongoing development and integration of these models into cancer studies are expected to drive transformative advancements in the field.

Induction of Tumor Ferroptosis-Dependent Immunity via an Injectable Attractive Pickering Emulsion Gel.

The combination of ferroptosis inducers and immune checkpoint blockade can enhance antitumor effects. However, the efficacy in tumors with low immunogenicity requires further investigation. In this work, a water-in-oil Pickering emulsion gel is developed to deliver (1S, 3R)-RSL-3 (RSL-3), a ferroptosis inducer dissolved in iodized oil, and programmed death-1 (PD-1) antibody, the most commonly used immune checkpoint inhibitor dissolved in water, with optimal characteristics (RSL-3 + PD-1@gel). Tumor lipase degrades the continuous oil phase, which results in the slow release of RSL-3 and PD-1 antibody and a notable antitumor effect against low-immunogenic hepatocellular carcinoma and pancreatic cancer. Intriguingly, the RSL-3 + PD-1@gel induces ferroptosis of tumor cells, resulting in antitumor immune response via accumulation of helper T lymphocyte cells and cytotoxic T cells. Additionally, the single-cell sequence profiling analysis during tumor treatment reveals the induction of ferroptosis in tumor cells together with strong antitumor immune response in ascites.

Impact of hydrogel biophysical properties on tumor spheroid growth and drug response.

The extracellular matrix (ECM) plays a critical role in regulating cell-matrix interactions during tumor progression. These interactions are due in large part to the biophysical properties responding to cancer cell interactions. Within in vitro models, the ECM is mimicked by hydrogels, which possess adjustable biophysical properties that are integral to tumor development. This work presents a systematic and comparative study on the impact of the biophysical properties of two widely used natural hydrogels, Matrigel and collagen gel, on tumor growth and drug response. The biophysical properties of Matrigel and collagen including complex modulus, loss tangent, diffusive permeability, and pore size, were characterised. Then the spheroid growth rates in these two hydrogels were monitored for spheroids with two different sizes (140 µm and 500 µm in diameters). An increased migratory growth was observed in the lower concentration of both the gels. The effect of spheroid incorporation within the hydrogel had a minimal impact on the hydrogel's complex modulus. Finally, 3D tumor models using different concentrations of hydrogels were applied for drug treatment using paclitaxel. Spheroids cultured in hydrogels with different concentrations showed different drug response, demonstrating the significant effect of the choice of hydrogels and their concentrations on the drug response results despite using the same spheroids. This study provides useful insights into the effect of hydrogel biophysical properties on spheroid growth and drug response and highlights the importance of hydrogel selection and in vitro model design.

Nanoparticle elasticity regulates the formation of cell membrane-coated nanoparticles and their nano-bio interactions.

Cell membrane-coated nanoparticles are emerging as a new type of promising nanomaterials for immune evasion and targeted delivery. An underlying premise is that the unique biological functions of natural cell membranes can be conferred on the inherent physiochemical properties of nanoparticles by coating them with a cell membrane. However, the extent to which the membrane protein properties are preserved on these nanoparticles and the consequent bio-nano interactions are largely unexplored. Here, we synthesized two mesenchymal stem cell (MSC) membrane-coated silica nanoparticles (MCSNs), which have similar sizes but distinctly different stiffness values (MPa and GPa). Unexpectedly, a much lower macrophage uptake, but much higher cancer cell uptake, was found with the soft MCSNs compared with the stiff MCSNs. Intriguingly, we discovered that the soft MCSNs enabled the forming of a more protein-rich membrane coating and that coating had a high content of the MSC chemokine CXCR4 and MSC surface marker CD90. This led to the soft MCSNs enhancing cancer cell uptake mediated by the CD90/integrin receptor-mediated pathway and CXCR4/SDF-1 pathways. These findings provide a major step forward in our fundamental understanding of how the combination of nanoparticle elasticity and membrane coating may be used to facilitate bio-nano interactions and pave the way forward in the development of more effective cancer nanomedicines.

Correlates of suicidal ideation in rural Chinese junior high school left-behind children: A socioecological resilience framework.

Introduction: Suicide is one of the top five causes of adolescent mortality around the world. The socioecological resilience framework in explaining the risk factors and protective factors for suicidal ideation in left-behind children (LBC) has not been well explored. The current study aims to compare the prevalence of suicidal ideation in LBC and non-LBC, and explore its correlations with resilience factors among LBC. Methodology: This study was part of an epidemiological survey conducted by UNICEF exploring mental health outcomes in left-behind children. We implemented a cross-sectional study collecting data from 11 provinces and 1 municipal, with 5,026 participants (3,359 LBC, 1,667 controls) in year one junior high school living in impoverished areas of rural China. Data on suicidal ideation, self-harm, resilience factors including health-risk behaviors, psychological wellbeing as it was measured by the Strengths and Difficulties Questionnaire, peer relationship within the school environment, and family support were collected. Results: Overall prevalence of suicidal ideation among LBC was 7.2% which is significantly different from 5.5% reported by NLBC (χ2 = 4.854, p = 0.028). LBC reported a higher prevalence of self-harm (16.4%) than NLBC (13.0%; χ2 = 10.232, p = 0.001), but there was no difference in the prevalence of suicide plan, suicide attempt or help-seeking. LBC had significantly poorer psychological feeling, and greater emotional and behavioral difficulties peer relationship in the school environment than controls. In the multiple logistic regression, history of self-harm was the greatest predictor for suicidal ideation among LBC (OR = 2.078, 95% CI: 1.394-3.100, p < 0.001). Health risk behavior including previous smoking attempt, poor psychological feeling, and emotional and behavior difficulties, and poor peer relationship within school environment, were also significant risk factors for suicidal ideation among LBC. Conclusion: The prevalence of suicidal ideation and self-harm was greater among left-behind than non-left-behind children. Our results show resilience factors including previous self-harm, emotional and behavioral problems, smoking, and poor peer relationship are significantly associated with suicidal ideation in left-behind adolescents.

Biophysical properties of hydrogels for mimicking tumor extracellular matrix.

The extracellular matrix (ECM) is an essential component of the tumor microenvironment. It plays a critical role in regulating cell-cell and cell-matrix interactions. However, there is lack of systematic and comparative studies on different widely-used ECM mimicking hydrogels and their properties, making the selection of suitable hydrogels for mimicking different in vivo conditions quite random. This study systematically evaluates the biophysical attributes of three widely used natural hydrogels (Matrigel, collagen gel and agarose gel) including complex modulus, loss tangent, diffusive permeability and pore size. A new and facile method was developed combining Critical Point Drying, Scanning Electron Microscopy imaging and a MATLAB image processing program (CSM method) for the characterization of hydrogel microstructures. This CSM method allows accurate measurement of the hydrogel pore size down to nanometer resolution. Furthermore, a microfluidic device was implemented to measure the hydrogel permeability (Pd) as a function of particle size and gel concentration. Among the three gels, collagen gel has the lowest complex modulus, medium pore size, and the highest loss tangent. Agarose gel exhibits the highest complex modulus, the lowest loss tangent and the smallest pore size. Collagen gel and Matrigel produced complex moduli close to that estimated for cancer ECM. The Pd of these hydrogels decreases significantly with the increase of particle size. By assessing different hydrogels' biophysical characteristics, this study provides valuable insights for tailoring their properties for various three-dimensional cancer models.

Nanocarrier-Based Tumor-Targeting Drug Delivery Systems for Hepatocellular Carcinoma Treatments: Enhanced Therapeutic Efficacy and Reduced Drug Toxicity.

Hepatocellular carcinoma (HCC), due to the lack of efficient diagnostic methods and short of available treatments, becomes the third main cause of cancer deaths. Novel treatments for HCCs are thus in great need. The fast-growing area of drug delivery provides intriguing possibility to design nanocarriers with unique properties. The nanocarriers performanced as drug deliver vehicles enable the design of diverse drug delivery systems, which could serve multiple purposes, including improved bioavailability, controlled or triggered release and targeted delivery, leading to enhanced drug efficacy and lowered drug toxicity. This paper provides an overview on the types of delivery vehicles, functions of drug nanocarriers and types of ligand-based targeting systems and highlights the advances made towards better HCC treatments.

Facile bioinspired synthesis of iron oxide encapsulating silica nanocapsules.

Iron oxide nanoparticles have been extensively studied for a wide variety of applications. However, there remains a challenge in developing hierarchical magnetic iron oxide nanoparticles as existing synthetic techniques require harsh, toxic chemical conditions and high temperatures or give poorly defined product with weak magnetic properties. In addition, drug loading is limited to post-loading methods such as chemical conjugation or surface adsorption that have poor loading efficiency and are prone to premature drug release. We report a facile biomimetic method for making iron oxide nanoparticle-loaded silica nanocapsules based on a bimodal catalytic peptide surfactant stabilized nanoemulsion template. Iron oxide nanoparticles can be preloaded into the oil phase of the nanoemulsion at tunable concentrations, and the excellent surface activity of the designed bimodal peptide in combination with sufficient electrostatic repulsion promotes the stability of the nanoemulsions. Biosilicification induced by the catalytic peptide module leads to the formation of silica shell nanocapsules containing a magnetic oil core. The bioinspired silica nanocapsules encapsulating iron oxide nanoparticles demonstrate the next-generation of magnetic nanostructures for drug delivery applications.

Liver organoid as a 3D in vitro model for drug validation and toxicity assessment.

The past decade has seen many advancements in the development of three-dimensional (3D) in vitro models in pharmaceutical sciences and industry. Specifically, organoids present a self-organising, self-renewing and more physiologically relevant model than conventional two-dimensional (2D) cell cultures. Liver organoids have been developed from a variety of cell sources, including stem cells, cell lines and primary cells. They have potential for modelling patient-specific disease and establishing personalised therapeutic approaches. Additionally, liver organoids have been used to test drug efficacy and toxicity. Herein we summarise cell sources for generating liver organoids, the advantages and limitations of each cell type, as well as the application of the organoids in modelling liver diseases. We focus on the use of liver organoids as tools for drug validation and toxicity assessment.

Nanoparticle-Stabilized Oxygen Microcapsules Prepared by Interfacial Polymerization for Enhanced Oxygen Delivery.

Most tumors have more severe hypoxia levels than normal tissue; tumor hypoxia is thus a useful target for cancer treatment. Here, we develop an effective oxygen delivery vehicle of polydopamine-nanoparticle-stabilized oxygen microcapsules by interfacial polymerization. The oxygen microcapsules have excellent biocompatibility. Oxygen could easily diffuse out from the microcapsules, thus increasing and maintaining the microenvironment at an oxygen-rich state. In vitro cell cultures confirm that oxygen microcapsules could effectively improve the hypoxia microenvironment, showing the lowest fluorescent intensity of hypoxia-green-labeled cells. When injected subcutaneously in vivo, oxygen microcapsules could also improve the tumor's hypoxia microenvironment, thus suppressing the growth of tumor. Synergetic therapy using oxygen microcapsules and gemcitabine drugs is an effective way for tumor treatment, showing the best performance in suppressing the tumor's growth.

Biomimetic core-shell silica nanoparticles using a dual-functional peptide.

Biomimetic nanomaterials have attracted tremendous research interest in the past decade. We recently developed biomimetic core-shell nanoparticles - silica nanocapsules, using a designer dual-functional peptide SurSi under room temperature, neutral pH and without use of any toxic reagents or chemicals. The SurSi peptide is designed capable of not only stabilizing nanoemulsions because of its excellent surface activity, but also inducing the formation of silica through biosilicification at an oil-water interface. However, it remains challenging to precisely control the peptide-induced nucleation and biosilicification specifically at the oil-water interface, thus forming oil-core silica-shell nanocapsules with uniform size and monodispersity. In this study, the fundamental mechanism of silica formation through a peptide catalyzed biosilicification was systematically investigated, so that the formation of oil-core silica-shell nanocapsules can be precisely controlled. The SurSi peptide induced hydrolysis and nucleation of biomineralized silica particles were monitored to study the biosilicification kinetics. Effects of pH, SurSi peptide concentration and pre-hydrolysis of silica precursors were also studied to optimize the formation of biomimetic silica nanocapsules. The fundamental understanding achieved through these systematic studies provides valuable insights for making core-shell nanoparticles via controlling nucleation and reaction at interfaces.

NIR-II bioluminescence for in vivo high contrast imaging and in situ ATP-mediated metastases tracing.

Bioluminescence imaging has been widely used in life sciences and biomedical applications. However, conventional bioluminescence imaging usually operates in the visible region, which hampers the high-performance in vivo optical imaging due to the strong tissue absorption and scattering. To address this challenge, here we present bioluminescence probes (BPs) with emission in the second near infrared (NIR-II) region at 1029 nm by employing bioluminescence resonance energy transfer (BRET) and two-step fluorescence resonance energy transfer (FRET) with a specially designed cyanine dye FD-1029. The biocompatible NIR-II-BPs are successfully applied to vessels and lymphatics imaging in mice, which gives ~5 times higher signal-to-noise ratios and ~1.5 times higher spatial resolution than those obtained by NIR-II fluorescence imaging and conventional bioluminescence imaging. Their capability of multiplexed imaging is also well displayed. Taking advantage of the ATP-responding character, the NIR-II-BPs are able to recognize tumor metastasis with a high tumor-to-normal tissue ratio at 83.4.

Active Encapsulation in Biocompatible Nanocapsules.

Co-precipitation is generally refers to the co-precipitation of two solids and is widely used to prepare active-loaded nanoparticles. Here, it is demonstrated that liquid and solid can precipitate simultaneously to produce hierarchical core-shell nanocapsules that encapsulate an oil core in a polymer shell. During the co-precipitation process, the polymer preferentially deposits at the oil/water interface, wetting both the oil and water phases; the behavior is determined by the spreading coefficients and driven by the energy minimization. The technique is applicable to directly encapsulate various oil actives and avoid the use of toxic solvent or surfactant during the preparation process. The obtained core-shell nanocapsules harness the advantage of biocompatibility, precise control over the shell thickness, high loading capacity, high encapsulation efficiency, good dispersity in water, and improved stability against oxidation. The applications of the nanocapsules as delivery vehicles are demonstrated by the excellent performances of natural colorant and anti-cancer drug-loaded nanocapsules. The core-shell nanocapsules with a controlled hierarchical structure are, therefore, ideal carriers for practical applications in food, cosmetics, and drug delivery.

Nanoparticle elasticity regulates phagocytosis and cancer cell uptake.

The ability of cells to sense external mechanical cues is essential for their adaptation to the surrounding microenvironment. However, how nanoparticle mechanical properties affect cell-nanoparticle interactions remains largely unknown. Here, we synthesized a library of silica nanocapsules (SNCs) with a wide range of elasticity (Young's modulus ranging from 560 kPa to 1.18 GPa), demonstrating the impact of SNC elasticity on SNC interactions with cells. Transmission electron microscopy revealed that the stiff SNCs remained spherical during cellular uptake. The soft SNCs, however, were deformed by forces originating from the specific ligand-receptor interaction and membrane wrapping, which reduced their cellular binding and endocytosis rate. This work demonstrates the crucial role of the elasticity of nanoparticles in modulating their macrophage uptake and receptor-mediated cancer cell uptake, which may shed light on the design of drug delivery vectors with higher efficiency.

A general approach for biomimetic mineralization of MOF particles using biomolecules.

Biomineralization of metal organic frameworks (MOFs) using biomolecules has recently attracted significant interest because of the benign process including room temperature, neutral pH and without the requirement of any other chemical reagents. Also, these biomolecule incorporated MOFs (biomolecules@MOFs) have demonstrated their potential in biomolecule encapsulation, protection and controlled release. This work aims to develop a general strategy to make biomolecules@MOFs via a biomimetic mineralization process. A library of biomolecules (peptides and proteins) with different charges were systematically studied to fundamentally understand the role of biomolecules and their proprieties in biomolecule-mediated MOF biomineralization. Biomolecule charge, amino acid sequence and stirring speed have been demonstrated to play important roles in controlling biomineralization reaction rate, particle shape and morphology.

Sustained-release ketamine-loaded nanoparticles fabricated by sequential nanoprecipitation.

Ketamine in sub-anaesthetic doses is an analgesic adjuvant with a morphine-sparing effect. Co-administration of a strong opioid with an analgesic adjuvant such as ketamine is a potential treatment option, especially for patients with cancer-related pain. A limitation of ketamine is its short in vivo elimination half-life. Hence, our aim was to develop biocompatible and biodegradable ketamine-loaded poly(ethylene glycol) (PEG)-block-poly(lactic-co-glycolic acid) (PLGA) nanoparticles for sustained release. Ketamine-encapsulated single polymer PEG-PLGA nanoparticles and double polymer PEG-PLGA/shellac (SH) nanoparticles with a high drug loading of 41.8% (drug weight/the total weight of drug-loaded nanoparticles) were prepared using a new sequential nanoprecipitation method. These drug-loaded nanoparticles exhibited a sustained-release profile for up to 21 days in vitro and for more than 5 days after intravenous injection in mice. Our study demonstrates that high drug loading and a sustained release profile can be achieved with ketamine-loaded PEG-PLGA nanoparticles prepared using this new nanoprecipitation method.

Therapeutic modulators of hepatic stellate cells for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of primary tumor in the liver and is a leading cause of cancer-related death worldwide. Activated hepatic stellate cells (HSCs) are key components of the HCC microenvironment and play an important role in the onset and progression of HCC through the secretion of growth factors and cytokines. Current treatment modalities that include chemotherapy, radiotherapy and ablation are able to activate HSCs and remodel the tumor microenvironment. Growing evidence has demonstrated that the complex interaction between activated HSCs and tumor cells can facilitate cancer chemoresistance and metastasis. Therefore, therapeutic targeting of activated HSCs has emerged as a promising strategy to improve treatment outcomes for HCC. This review summarizes the molecular mechanisms of HSC activation triggered by treatment modalities, the function of activated HSCs in HCC, as well as the crosstalk between tumor cells and activated HSCs. Pathways of activated HSC reduction are discussed, including inhibition, apoptosis, and reversion to the inactivated state. Finally, we outline the progress and challenges of therapeutic approaches targeting activated HSCs in the development of HCC treatment.

Tumor-Microenvironment-on-a-Chip for Evaluating Nanoparticle-Loaded Macrophages for Drug Delivery.

Targeted drug delivery remains attractive but challenging for cancer therapy. Cell-mediated drug delivery has emerged as a promising strategy to improve targeted drug delivery to tumors due to the intrinsic ability of certain types of cells (e.g., macrophage) to pass through physiological barriers and specifically home to tumors. To fundamentally understand how macrophage-based drug carriers transport and interact with the tumor microenvironment, we developed a tumor-microenvironment-on-a-chip (TMOC) model that enables the coculture of tumor spheroids and macrophages in a three-dimensional (3D) gel matrix. By introducing drug-loaded macrophages, the TMOC model allows real-time observation of macrophage migration toward the tumor, infiltration into tumor spheroids, and subsequent response of tumor to drugs. Our results demonstrated the superior capability of macrophages migrating toward the tumor and infiltrate tumor spheroids. Drug loading in macrophages had minimum effect on their cell viability, and drug-carrying macrophages exhibited greater tumor cell cytotoxicity compared to their nanoparticle counterparts. Our work highlighted the great potential of macrophages as novel drug carriers for targeted drug delivery, and the TMOC model serves as a versatile platform to enable quick evaluation of such cell-mediated drug delivery systems.

Bioinspired Core-Shell Nanoparticles for Hydrophobic Drug Delivery.

A large range of nanoparticles have been developed to encapsulate hydrophobic drugs. However, drug loading is usually less than 10 % or even 1 %. Now, core-shell nanoparticles are fabricated having exceptionally high drug loading up to 65 % (drug weight/the total weight of drug-loaded nanoparticles) and high encapsulation efficiencies (>99 %) based on modular biomolecule templating. Bifunctional amphiphilic peptides are designed to not only stabilize hydrophobic drug nanoparticles but also induce biosilicification at the nanodrug particle surface thus forming drug-core silica-shell nanocomposites. This platform technology is highly versatile for encapsulating various hydrophobic cargos. Furthermore, the high drug loading nanoparticles lead to better in vitro cytotoxic effects and in vivo suppression of tumor growth, highlighting the significance of using high drug-loading nanoparticles.