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Abstract Given the prevalence of hematological conditions, surgeries, and trauma incidents, hemostats—therapeutics designed to control and arrest bleeding—are an important tool in patient care. The prophylactic and therapeutic use of hemostats markedly enhances survival rates and improves the overall quality of life of patients suffering from these conditions. Since their inception in the 1960s, hemostats have witnessed remarkable progress in terms of the active ingredients utilized, therapeutic outcomes, demonstrated efficacy, and the storage stability. In this review, we provide a comprehensive analysis of commercially available hemostats approved by the FDA, along with newer investigative hemostats currently in active clinical trials. We delve into the modality of active ingredients, route of administration, formulation type, and disease indications of these approved and investigative hemostats. Further, we analyze the trends observed in the hemostat actives for Hemophilia A and B, concluding with insights into the emerging patterns and noteworthy developments to watch for in this dynamic field.

Abstract Hydrogels have been used in the clinic since the late 1980s with broad applications in drug delivery, cosmetics, tissue regeneration, among many other areas. The past three decades have witnessed rapid advances in the fields of polymer chemistry, crosslinking approaches, and hydrogel fabrication methods, which have collectively brought many new hydrogel products, either injectable or non‐injectable, to clinical studies. In an article published in 2020 entitled “Hydrogels in the clinic”, we reviewed the clinical landscape and translational challenges of injectable hydrogels. Here, we provide an update on the advances in the field and also extend the scope to include non‐injectable hydrogels. We highlight recently approved hydrogel products, provide an update on the clinical trials of injectable hydrogels, and discuss active clinical trials of topically applied and implantable hydrogels.

Abstract Antibody‐drug conjugates (ADCs), chemotherapeutic agents conjugated to an antibody to enhance their targeted delivery to tumors, represent a significant advancement in cancer therapy. ADCs combine the precise targeting capabilities of antibodies and the potent cell‐killing effects of chemotherapy, allowing for enhanced cytotoxicity to tumors while minimizing damage to healthy tissues. Here, we provide an overview of the current clinical landscape of ADCs, highlighting 11 U.S. Food and Drug Administration (FDA)‐approved products and discussing over 500 active clinical trials investigating newer ADCs. We also discuss some key challenges associated with the clinical translation of ADCs and highlight emerging strategies to overcome these hurdles. Our discussions will provide useful guidelines for the future development of safer and more effective ADCs for a broader range of indications.

Human activity recognition by radar sensors plays an important role in healthcare and smart homes. However, labeling a large number of radar datasets is difficult and time-consuming, and it is difficult for models trained on insufficient labeled data to obtain exact classification results. In this paper, we propose a multiscale residual weighted classification network with large-scale, medium-scale, and small-scale residual networks. Firstly, an MRW image encoder is used to extract salient feature representations from all time-Doppler images through contrastive learning. This can extract the representative vector of each image and also obtain the pre-training parameters of the MRW image encoder. During the pre-training process, large-scale residual networks, medium-scale residual networks, and small-scale residual networks are used to extract global information, texture information, and semantic information, respectively. Moreover, the time–channel weighting mechanism can allocate weights to important time and channel dimensions to achieve more effective extraction of feature information. The model parameters obtained from pre-training are frozen, and the classifier is added to the backend. Finally, the classifier is fine-tuned using a small amount of labeled data. In addition, we constructed a new dataset with eight dangerous activities. The proposed MRW-CN model was trained on this dataset and achieved a classification accuracy of 96.9%. We demonstrated that our method achieves state-of-the-art performance. The ablation analysis also demonstrated the role of multi-scale convolutional kernels and time–channel weighting mechanisms in classification.

Abstract Adjuvants, materials added to vaccines to enhance the resulting immune response, are important components of vaccination that are many times overlooked. While vaccines always include an antigen to tell the body what to vaccinate to, of equal importance the adjuvant provides the how, a significant factor in producing a complete response. The adjuvant space has been slow to develop with the first use of an adjuvant in a licensed vaccine occurring in the 1930s, and remaining the only adjuvant in licensed vaccines for the next 80 years. However, with vaccination at the forefront of protection against new and complex pathogens, it is important to consider all components when designing an effective vaccine. Here we summarize the adjuvant space in licensed vaccines as well as the novel adjuvant space in clinical trials with a specific focus on the materials utilized and their resulting impact on the immune response. We discuss five major categories of adjuvant materials: aluminum salts, nanoparticles, viral vectors, TLR agonists, and emulsions. For each category, we delve into the current clinical trials space, the impact of these materials on vaccination, as well as some of the ways in which they could be improved. Adjuvants present an exciting opportunity to improve vaccine responses and stability, this review will help inform about the current progress of this space. Translational impact statement In the aftermath of the COVID‐19 pandemic, vaccines for infectious diseases have come into the spotlight. While antigens have always been an important focus of vaccine design, the adjuvant is a significant tool for enhancing the immune response to the vaccine that has been largely underdeveloped. This article provides a broad review of the history of adjuvants and, the current vaccine adjuvant space, and the progress seen in adjuvants in clinical trials. There is specific emphasis on the material landscape for adjuvants and their resulting mechanism of action. Looking ahead, while the novel vaccine adjuvant space features exciting new technologies and materials, there is still a need for more to meet the protective needs of new and complex pathogens.

Pulmonary hypertension (PH) is an insidious pulmonary vasculopathy with high mortality and morbidity and its underlying pathogenesis is still poorly delineated. The hyperproliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs) contributes to pulmonary vascular remodeling in pulmonary hypertension, which is closely linked to the downregulation of fork-head box transcriptional factor O1 (FoxO1) and apoptotic protein caspase 3 (Cas-3). Here, PA-targeted co-delivery of a FoxO1 stimulus (paclitaxel, PTX) and Cas-3 was exploited to alleviate monocrotaline-induced pulmonary hypertension. The co-delivery system is prepared by loading the active protein on paclitaxel-crystal nanoparticles, followed by a glucuronic acid coating to target the glucose transporter-1 on the PASMCs. The co-loaded system (170 nm) circulates in the blood over time, accumulates in the lung, effectively targets the PAs, and profoundly regresses the remodeling of pulmonary arteries and improves hemodynamics, leading to a decrease in pulmonary arterial pressure and Fulton's index. Our mechanistic studies suggest that the targeted co-delivery system alleviates experimental pulmonary hypertension primarily via the regression of PASMC proliferation by inhibiting cell cycle progression and promoting apoptosis. Taken together, this targeted co-delivery approach offers a promising avenue to target PAs and cure the intractable vasculopathy in pulmonary hypertension.

Abstract Vaccines are an important tool in the rapidly evolving repertoire of immunotherapies in oncology. Although cancer vaccines have been investigated for over 30 years, very few have achieved meaningful clinical success. However, recent advances in areas such antigen identification, formulation development and manufacturing, combination therapy regimens, and indication and patient selection hold promise to reinvigorate the field. Here, we provide a timely update on the clinical status of cancer vaccines. We identify and critically analyze 360 active trials of cancer vaccines according to delivery vehicle, antigen type, indication, and other metrics, as well as highlight eight globally approved products. Finally, we discuss current limitations and future applications for clinical translation of cancer vaccines.

Abstract The covalent attachment of polyethylene glycol (PEG) to therapeutic agents, termed PEGylation, is a well‐established and clinically proven drug delivery approach to improve the pharmacokinetics and pharmacodynamics of drugs. Specifically, PEGylation can improve the parent drug's solubility, extend its circulation time, and reduce its immunogenicity, with minimal undesirable properties. PEGylation technology has been applied to various therapeutic modalities including small molecules, aptamers, peptides, and proteins, leading to over 30 PEGylated drugs currently used in the clinic and many investigational PEGylated agents under clinical trials. Here, we summarize the diverse types of PEGylation strategies, the key advantages of PEGylated therapeutics over their parent drugs, and the broad applications and impacts of PEGylation in clinical settings. A particular focus has been given to the size, topology, and functionalities of PEG molecules utilized in clinically used PEGylated drugs, as well as those under clinical trials. An additional section has been dedicated to analyzing some representative PEGylated drugs that were discontinued at different stages of clinical studies. Finally, we critically discuss the current challenges faced in the development and clinical translation of PEGylated agents.

Cellular nanovesicles which are referred to as cell-derived, nanosized lipid bilayer structures, have emerged as a promising platform for regulating immune responses. Owing to their outstanding advantages such as high biocompatibility, prominent structural stability, and high loading capacity, cellular nanovesicles are suitable for delivering various immunomodulatory molecules, such as small molecules, nucleic acids, peptides, and proteins. Immunomodulation induced by cellular nanovesicles has been exploited to modulate immune cell behaviors, which is considered as a novel cell-free immunotherapeutic strategy for the prevention and treatment of diverse diseases. Here we review emerging concepts and new advances in leveraging cellular nanovesicles to activate or suppress immune responses, with the aim to explicate their applications for immunomodulation. We overview the general considerations and principles for the design of engineered cellular nanovesicles with tailored immunomodulatory activities. We also discuss new advances in engineering cellular nanovesicles as immunotherapies for treating major diseases.

Crowd movement analysis (CMA) is a key technology in the field of public safety. This technology provides reference for identifying potential hazards in public places by analyzing crowd aggregation and dispersion behavior. Traditional video processing techniques are susceptible to factors such as environmental lighting and depth of field when analyzing crowd movements, so cannot accurately locate the source of events. Radar, on the other hand, offers all-weather distance and angle measurements, effectively compensating for the shortcomings of video surveillance. This paper proposes a crowd motion analysis method based on radar particle flow (RPF). Firstly, radar particle flow is extracted from adjacent frames of millimeter-wave radar point sets by utilizing the optical flow method. Then, a new concept of micro-source is defined to describe whether any two RPF vectors originated from or reach the same location. Finally, in each local area, the internal micro-sources are counted to form a local diffusion potential, which characterizes the movement state of the crowd. The proposed algorithm is validated in real scenarios. By analyzing and processing radar data on aggregation, dispersion, and normal movements, the algorithm is able to effectively identify these movements with an accuracy rate of no less than 88%.

Abstract Digital therapeutics are emerging as a new form of therapeutic interventions. Unlike conventional therapeutics, digital therapeutics deliver interventions directly to patients using an evidence‐based, clinically evaluated software to treat, manage, or prevent diseases. Digital therapeutics manifest in diverse forms such as web‐based applications, mobile applications on smart devices, virtual reality, and video games. As its own product category for FDA approval, digital therapeutics can function as stand‐alone treatments or in combination with conventional therapeutics to improve adherence and/or efficacy. Here, we review the clinical landscape of digital therapeutics. We summarize FDA‐approved products and their clinical use, overview >300 ongoing clinical trials, and discuss challenges for their clinical translation and strategies to overcome the same.

Abstract Cell‐based therapies comprising the administration of living cells to patients for direct therapeutic activities have experienced remarkable success in the clinic, of which macrophages hold great potential for targeted drug delivery due to their inherent chemotactic mobility and homing ability to tumors with high efficiency. However, such targeted delivery of drugs through cellular systems remains a significant challenge due to the complexity of balancing high drug‐loading with high accumulations in solid tumors. Herein, a tumor‐targeting cellular drug delivery system (MAGN) by surface engineering of tumor‐homing macrophages (Mφs) with biologically responsive nanosponges is reported. The pores of the nanosponges are blocked with iron‐tannic acid complexes that serve as gatekeepers by holding encapsulated drugs until reaching the acidic tumor microenvironment. Molecular dynamics simulations and interfacial force studies are performed to provide mechanistic insights into the “ON‐OFF” gating effect of the polyphenol‐based supramolecular gatekeepers on the nanosponge channels. The cellular chemotaxis of the Mφ carriers enabled efficient tumor‐targeted delivery of drugs and systemic suppression of tumor burden and lung metastases in vivo. The findings suggest that the MAGN platform offers a versatile strategy to efficiently load therapeutic drugs to treat advanced metastatic cancers with a high loading capacity of various therapeutic drugs.

Abstract Red blood cell (RBC) hitchhiking has great potential in enhancing drug therapy, by improving targeting and reducing rapid clearance of nanoparticles (NPs). However, to improve the potential for clinical translation of RBC hitchhiking, a more thorough understanding of the RBC-NP interface is needed. Here, we evaluate the effects of NP surface parameters on the success and biocompatibility of NP adsorption to extracted RBCs from various species. Major differences in RBC characteristics between rabbit, mouse and human were proven to significantly impact NP adsorption outcomes. Additionally, the effects of NP design parameters, including NP hydrophobicity, zeta potential, surfactant concentration and drug encapsulation, on RBC hitchhiking are investigated. Our studies demonstrate the importance of electrostatic interactions in balancing NP adsorption success and biocompatibility. We further investigated the effect of varying the anti-coagulant used for blood storage. The results presented here offer new insights into the parameters that impact NP adsorption on RBCs that will assist researchers in experimental design choices for using RBC hitchhiking as drug delivery strategy.

Abstract Uncontrolled bleeding is a life‐threatening emergency that requires immediate intervention. Currently available on‐site bleeding interventions largely rely on the use of tourniquets, pressure dressing, and other topical hemostatic agents, which can only treat bleeding injuries that are known, accessible, and potentially compressible. Synthetic hemostats that are stable at room temperature, easy to carry, field‐usable, and able to stop internal bleeding at multiple or unknown sources, are still lacking. We recently developed a hemostatic agent via polymer peptide interfusion (HAPPI), which can selectively bind to activated platelets and injury sites after intravascular administration. Here we report that HAPPI is highly effective in treating multiple lethal traumatic bleeding conditions in normal as well as hemophilia models via either systemic administration or topical application. In a rat liver traumatic model, intravenous injection of HAPPI resulted in a significant decrease in blood loss and a four‐fold reduction in mortality rate within 2 h after injury. When applied topically on liver punch biopsy wounds in heparinized rats, HAPPI achieved a 73% of reduction in blood loss and a five‐fold increase in survival rate. HAPPI also exhibited hemostatic efficacy in hemophilia A mice by reducing blood loss. Further, HAPPI worked synergistically with rFVIIa to induce immediate hemostasis and 95% reduction in total blood loss compared to the saline‐treated group in hemophelia mice models. These results demonstrate that HAPPI is a promising field‐usable hemostatic agent for a broad range of different hemorrhagic conditions.

Abstract Ribonucleic acid (RNA) therapeutics are being actively researched as a therapeutic modality in preclinical and clinical studies. They have become one of the most ubiquitously known and discussed therapeutics in recent years in part due to the ongoing coronavirus pandemic. Since the first approval in 1998, research on RNA therapeutics has progressed to discovering new therapeutic targets and delivery strategies to enhance their safety and efficacy. Here, we provide an overview of the current clinically relevant RNA therapeutics, mechanistic basis of their function, and strategies to improve their clinical use. We discuss the 17 approved RNA therapeutics and perform an in‐depth analysis of the 222 ongoing clinical trials, with an emphasis on their respective mechanisms and disease areas. We also provide perspectives on the challenges for clinical translation of RNA therapeutics and suggest potential strategies to address these challenges.

Abstract Alzheimer's disease (AD) and Parkinson's disease (PD) are the most prevalent neurodegenerative diseases, affecting millions and costing billions each year in the United States alone. Despite tremendous progress in developing therapeutics that manage the symptoms of these two diseases, the scientific community has yet to develop a treatment that effectively slows down, inhibits, or cures neurodegeneration. To gain a better understanding of the current therapeutic frontier for the treatment of AD and PD, we provide a review on past and present therapeutic strategies for these two major neurodegenerative disorders in the clinical trial process. We briefly recap currently US Food and Drug Administration‐approved therapies, and then explore trends in clinical trials across the variables of therapy mechanism of disease intervention, administration route, use of delivery vehicle, and outcome measures, across the clinical phases over time for “Drug” and “Biologic” therapeutics. We then present the success rate of past clinical trials and analyze the intersections in therapeutic approaches for AD and PD, revealing the shift in clinical trials away from therapies targeting neurotransmitter systems that provide symptomatic relief, and towards anti‐aggregation, anti‐inflammatory, anti‐oxidant, and regeneration strategies that aim to inhibit the root causes of disease progression. We also highlight the evolving distribution of the types of “Biologic” therapies investigated, and the slowly increasing yet still severe under‐utilization of delivery vehicles for AD and PD therapeutics. We then briefly discuss novel preclinical strategies for treating AD and PD. Overall, this review aims to provide a succinct overview of the clinical landscape of AD and PD therapies to better understand the field's therapeutic strategy in the past and the field's evolution in approach to the present, to better inform how to effectively treat AD and PD in the future.

This paper proposes a fast direction of arrival (DOA) estimation method based on positive incremental modified Cholesky decomposition atomic norm minimization (PI-CANM) for augmented coprime array sensors. The approach incorporates coprime sampling on the augmented array to generate a non-uniform, discontinuous virtual array. It then utilizes interpolation to convert this into a uniform, continuous virtual array. Based on this, the problem of DOA estimation is equivalently formulated as a gridless optimization problem, which is solved via atomic norm minimization to reconstruct a Hermitian Toeplitz covariance matrix. Furthermore, by positive incremental modified Cholesky decomposition, the covariance matrix is transformed from positive semi-definite to positive definite, which simplifies the constraint of optimization problem and reduces the complexity of the solution. Finally, the Multiple Signal Classification method is utilized to carry out statistical signal processing on the reconstructed covariance matrix, yielding initial DOA angle estimates. Experimental outcomes highlight that the PI-CANM algorithm surpasses other algorithms in estimation accuracy, demonstrating stability in difficult circumstances such as low signal-to-noise ratios and limited snapshots. Additionally, it boasts an impressive computational speed. This method enhances both the accuracy and computational efficiency of DOA estimation, showing potential for broad applicability.

Invasive fungal infections (IFIs) represent a growing public concern for clinicians to manage in many medical settings, with substantial associated morbidities and mortalities. Among many current therapeutic options for the treatment of IFIs, amphotericin B (AmB) is the most frequently used drug. AmB is considered as a first-line drug in the clinic that has strong antifungal activity and less resistance. In this review, we summarized the most promising research efforts on nanocarriers for AmB delivery and highlighted their efficacy and safety for treating IFIs. We have also discussed the mechanism of actions of AmB, rationale for treating IFIs, and recent advances in formulating AmB for clinical use. Finally, this review discusses some practical considerations and provides recommendations for future studies in applying AmB for combating IFIs.

As an important technology in 3D vision, point-cloud registration has broad development prospects in the fields of space-based remote sensing, photogrammetry, robotics, and so on. Of the available algorithms, the Iterative Closest Point (ICP) algorithm has been used as the classic algorithm for solving point cloud registration. However, with the point cloud data being under the influence of noise, outliers, overlapping values, and other issues, the performance of the ICP algorithm will be affected to varying degrees. This paper proposes a global structure and adaptive weight aware ICP algorithm (GSAW-ICP) for image registration. Specifically, we first proposed a global structure mathematical model based on the reconstruction of local surfaces using both the rotation of normal vectors and the change in curvature, so as to better describe the deformation of the object. The model was optimized for the convergence strategy, so that it had a wider convergence domain and a better convergence effect than either of the original point-to-point or point-to-point constrained models. Secondly, for outliers and overlapping values, the GSAW-ICP algorithm was able to assign appropriate weights, so as to optimize both the noise and outlier interference of the overall system. Our proposed algorithm was extensively tested on noisy, anomalous, and real datasets, and the proposed method was proven to have a better performance than other state-of-the-art algorithms.

Abstract Adeno‐associated virus (AAV)‐mediated gene therapy is a promising therapeutic modality for curing many diseases including monogenic diseases. However, limited tissue‐targeting and restricted re‐administration due to the vector immunogenicity largely restrict its therapeutic potential. Here, using a red blood cell (RBC) as the carrier vehicle for AAV is demonstrated to improve its tissue‐targeted transduction and enable its re‐administration. Anchoring AAV to the RBC surface minimally affected its infectability toward endothelial cells. Meanwhile, AAV anchored onto RBCs is predominantly delivered to and shows efficient transduction in the lungs by virtue of the biophysical features of RBCs. RBC‐anchored AAVs lead to a four‐ to five‐fold enhancement in target gene expression in the lungsas compared to free AAVs following a single‐ or dual‐dosing regimen. While RBC anchoring does not prevent the induction of adaptive immune responses against AAV, it results in successful transgene expression upon re‐administration following prior AAV exposure. The ability to re‐administer is partially attributed to the delayed and reduced AAV neutralization by neutralizing antibodies, resulting from the combination of limited exposure of physically confined AAVs and the short time required to reach the lungs. This study's findings suggest that the RBC‐mediated approach is a promising strategy for repetitive, targeted AAV gene therapy.

This paper proposes a human activity recognition (HAR) method for frequency-modulated continuous wave (FMCW) radar sensors. The method utilizes a multi-domain feature attention fusion network (MFAFN) model that addresses the limitation of relying on a single range or velocity feature to describe human activity. Specifically, the network fuses time-Doppler (TD) and time-range (TR) maps of human activities, resulting in a more comprehensive representation of the activities being performed. In the feature fusion phase, the multi-feature attention fusion module (MAFM) combines features of different depth levels by introducing a channel attention mechanism. Additionally, a multi-classification focus loss (MFL) function is applied to classify confusable samples. The experimental results demonstrate that the proposed method achieves 97.58% recognition accuracy on the dataset provided by the University of Glasgow, UK. Compared to existing HAR methods for the same dataset, the proposed method showed an improvement of about 0.9–5.5%, especially in the classification of confusable activities, showing an improvement of up to 18.33%.

Abstract Gene therapies are currently one of the most investigated therapeutic modalities in both the preclinical and clinical settings and have shown promise in treating a diverse spectrum of diseases. Gene therapies aim at introducing a gene material in target cells and represent a promising approach to cure diseases that were thought to be incurable by conventional modalities. In many cases, a gene therapy requires a vector to deliver gene therapeutics into target cells; viral vectors are among the most widely studied vectors owing to their distinguished advantages such as outstanding transduction efficiency. With decades of development, viral vector‐based gene therapies have achieved promising clinical outcomes with many products approved for treating a range of diseases including cancer, infectious diseases and monogenic diseases. In addition, a number of active clinical trials are underway to further expand their therapeutic potential. In this review, we highlight the diversity of viral vectors, review approved products, and discuss the current clinical landscape of in vivo viral vector‐based gene therapies. We have reviewed 13 approved products and their clinical applications. We have also analyzed more than 200 active trials based on various viral vectors and discussed their respective therapeutic applications. Moreover, we provide a critical analysis of the major translational challenges for in vivo viral vector‐based gene therapies and discuss possible strategies to address the same.

Abstract Antiproliferative chemotherapeutic agents offer a potential effective treatment for inflammatory arthritis. However, their clinical application is limited by high systemic toxicity, low joint bioavailability as well as formulation challenges. Here, we report an intra‐articular drug delivery system combining hyaluronic acid hydrogels and drug nanocrystals to achieve localized and sustained delivery of an antiproliferative chemotherapeutic agent camptothecin for long‐term treatment of inflammatory arthritis. We synthesized a biocompatible, in situ‐forming injectable hyaluronic acid hydrogel using a naturally occurring click chemistry: cyanobenzothiazole/cysteine reaction, which is the last step reaction in synthesizing D‐luciferin in fireflies. This hydrogel was used to encapsulate camptothecin nanocrystals (size of 160–560 nm) which released free camptothecin in a sustained manner for 4 weeks. In vivo studies confirmed that the hydrogel remained in the joint over 4 weeks. By using the collagen‐induced arthritis rat model, we demonstrate that the hydrogel‐camptothecin formulation could alleviate arthritis severity as indicated by the joint size and interleukin‐1β level in the harvested joints, as well as from histological and microcomputed tomography evaluation of joints. The hydrogel‐nanocrystal formulation strategy described here offers a potential solution for intra‐articular therapy for inflammatory arthritis.

Abstract Cell therapies have emerged as a promising therapeutic modality with the potential to treat and even cure a diverse array of diseases. Cell therapies offer unique clinical and therapeutic advantages over conventional small molecules and the growing number of biologics. Particularly, living cells can simultaneously and dynamically perform complex biological functions in ways that conventional drugs cannot; cell therapies have expanded the spectrum of available therapeutic options to include key cellular functions and processes. As such, cell therapies are currently one of the most investigated therapeutic modalities in both preclinical and clinical settings, with many products having been approved and many more under active clinical investigation. Here, we highlight the diversity and key advantages of cell therapies and discuss their current clinical advances. In particular, we review 28 globally approved cell therapy products and their clinical use. We also analyze >1700 current active clinical trials of cell therapies, with an emphasis on discussing their therapeutic applications. Finally, we critically discuss the major biological, manufacturing, and regulatory challenges associated with the clinical translation of cell therapies.

Abstract Cancer therapy is increasingly shifting toward targeting the tumor immune microenvironment and influencing populations of tumor infiltrating lymphocytes. Breast cancer presents a unique challenge as tumors of the triple‐negative breast cancer subtype employ a multitude of immunosilencing mechanisms that promote immune evasion and rapid growth. Treatment of breast cancer with chemotherapeutics has been shown to induce underlying immunostimulatory responses that can be further amplified with the addition of immune‐modulating agents. Here, we investigate the effects of combining doxorubicin (DOX) and gemcitabine (GEM), two commonly used chemotherapeutics, with monophosphoryl lipid A (MPLA), a clinically used TLR4 adjuvant derived from liposaccharides. MPLA was incorporated into the lipid bilayer of liposomes loaded with a 1:1 molar ratio of DOX and GEM to create an intravenously administered treatment. In vivo studies indicated excellent efficacy of both GEM‐DOX liposomes and GEM‐DOX‐MPLA liposomes against 4T1 tumors. In vitro and in vivo results showed increased dendritic cell expression of CD86 in the presence of liposomes containing chemotherapeutics and MPLA. Despite this, a tumor rechallenge study indicated little effect on tumor growth upon rechallenge, indicating the lack of a long‐term immune response. GEM/DOX/MPLA‐L displayed remarkable control of the primary tumor growth and can be further explored for the treatment of triple‐negative breast cancer with other forms of immunotherapy.

Aimed at the problems in which the performance of filters derived from a hypothetical model will decline or the cost of time of the filters derived from a posterior model will increase when prior knowledge and second-order statistics of noise are uncertain, a new filter is proposed. In this paper, a Bayesian robust Kalman filter based on posterior noise statistics (KFPNS) is derived, and the recursive equations of this filter are very similar to that of the classical algorithm. Note that the posterior noise distributions are approximated by overdispersed black-box variational inference (O-BBVI). More precisely, we introduce an overdispersed distribution to push more probability density to the tails of variational distribution and incorporated the idea of importance sampling into two strategies of control variates and Rao–Blackwellization in order to reduce the variance of estimators. As a result, the convergence process will speed up. From the simulations, we can observe that the proposed filter has good performance for the model with uncertain noise. Moreover, we verify the proposed algorithm by using a practical multiple-input multiple-output (MIMO) radar system.

Liposome-based drug delivery systems have allowed for better drug tolerability and longer circulation times but are often optimized for a single agent due to the inherent difficulty of co-encapsulating two drugs with differing chemical profiles. Here, we design and test a prodrug based on a ribosylated nucleoside form of 5-fluorouracil, 5-fluorouridine (5FUR), with the final purpose of co-encapsulation with doxorubicin (DOX) in liposomes. To improve the loading of 5FUR, we developed two 5FUR prodrugs that involved the conjugation of either one or three moieties of tryptophan (W) known respectively as, 5FUR−W and 5FUR−W3. 5FUR−W demonstrated greater chemical stability than 5FUR−W3 and allowed for improved loading with fewer possible byproducts from tryptophan hydrolysis. Varied drug ratios of 5FUR−W: DOX were encapsulated for in vivo testing in the highly aggressive 4T1 murine breast cancer model. A liposomal molar ratio of 2.5 5FUR−W: DOX achieved a 62.6% reduction in tumor size compared to the untreated control group and a 33% reduction compared to clinical doxorubicin liposomes in a proof-of-concept study to demonstrate the viability of the co-encapsulated liposomes. We believe that the new prodrug 5FUR−W demonstrates a prodrug design with clinical translatability by reducing the number of byproducts produced by the hydrolysis of tryptophan, while also allowing for loading flexibility.

Red blood cells (RBC) have great potential as drug delivery systems, capable of producing unprecedented changes in pharmacokinetics, pharmacodynamics, and immunogenicity. Despite this great potential and nearly 50 years of research, it is only recently that RBC-mediated drug delivery has begun to move out of the academic lab and into industrial drug development. RBC loading with drugs can be performed in several ways—either via encapsulation within the RBC or surface coupling, and either ex vivo or in vivo—depending on the intended application. In this review, we briefly summarize currently used technologies for RBC loading/coupling with an eye on how pharmacokinetics is impacted. Additionally, we provide a detailed description of key ADME (absorption, distribution, metabolism, elimination) changes that would be expected for RBC-associated drugs and address unique features of RBC pharmacokinetics. As thorough understanding of pharmacokinetics is critical in successful translation to the clinic, we expect that this review will provide a jumping off point for further investigations into this area.