Samir Mitragotri

The clinical impact of gene therapies is constrained by poor delivery to target tissues beyond the liver after intravenous administration. Current molecular targeting strategies, such as capsid engineering or gene-carrier surface modification, have achieved only limited success due to their inability to overcome the hierarchical barriers from injection to deep tissue transduction. Here, we introduce a Multiscale Approach using RBC-mediated hitchhiking and Vascular Endothelium Leakage (MARVEL), which integrates red blood cell hitchhiking with VEGF-induced vascular permeabilization to enhance accumulation and penetration of cargoes. Using adeno-associated viruses (AAVs) as a model, MARVEL markedly increases AAV localization in the lungs, improves endothelial transcytosis, and enables gene expression in deeper tissue layers while maintaining a favorable safety profile. We further demonstrate that MARVEL can be adopted into an in situ hitchhiking approach, bypassing the need for ex vivo formulation. MARVEL provides a scalable strategy to address long-standing delivery challenges in gene therapy.

T cells, as one of the most abundant immune cell types in the human body, play a central role in therapeutic applications and currently dominate the clinical landscape of cell therapies. Their target specificity and capacity to generate durable therapeutic responses make them a powerful modality for precision therapy. T cell therapies represent a leading frontier in cellular medicine and have been investigated for a broad spectrum of indications, from cancers to autoimmune diseases. Here, we provide a detailed overview of the clinical landscape of T cell therapies. We outline the historical developments that shaped the evolution of T cells into transformative therapies and present a comprehensive analysis of their clinical translation. We discuss key milestones in T cell discovery and provide an overview of the 19 globally approved T cell therapy products. We then examine the core features of these approved products and conduct an in-depth analysis of 2570 clinical trials involving T cell therapies, identifying three distinct time intervals of growth in clinical activity. Furthermore, we evaluate the evolution of critical trial parameters, such as cell source, disease indication, target selection, and delivery route, highlighting emerging trends and key inflection points. Lastly, we discuss the biological and logistical challenges that limit the broader clinical translation of T cell therapies to new indications and diverse patient populations. Our findings indicate a steady rise in clinical studies and regulatory approvals for T cell therapies, with a notably higher rate of approved products in recent years compared to stem cell therapies. This growth exhibits a phased pattern, with each interval characterized by a major inflection point in scientific advancement and clinical translation. Our discussions will provide a quantitative and contextualized overview of this clinical progress in T cell therapy, offering insights into its current trajectory and future potential as a transformative class of therapeutics.

Abstract Bloodstream infections (BSI) are a leading cause of mortality and morbidity in both civilian and military populations. Immunocompromised patients in hospital settings are susceptible to nosocomial infections and subsequently complex disease states such as sepsis and shock. Similarly, civilians and service members wounded from insults such as penetrating wounds, burn, and blast suffer transient immune dysregulation and are thus susceptible to infections from various pathogens. The current standard of care to prevent severe disease arising from BSI in these scenarios is some combination of time‐consuming diagnosis, periodic monitoring to identify symptomology, and ultimately treatment using high doses of antimicrobial compounds. However, state‐of‐the‐art approaches to monitor and treat BSI are burdensome, untimely, and reactive. Shortcomings with current approaches demand alternative strategies to treat BSI early thus preventing more advanced disease states. This review paper summarizes recent progress in novel treatment strategies to manage BSI arising from both bacterial and fungal pathogens. These approaches include novel molecules to confer protection by supplementing host‐directed immunity using various therapeutic interventions. Specifically, novel peptide‐based compounds, engineered extracellular vesicles, and synthetic microparticles will be discussed.

Bioelectronic implants for brain stimulation are used to treat brain disorders but require invasive surgery. To provide a noninvasive alternative, we report nonsurgical implants consisting of immune cell-electronics hybrids, an approach we call Circulatronics. The devices can be delivered intravenously and traffic autonomously to regions of inflammation in the brain, where they implant and enable neuromodulation, circumventing the need for surgery. To achieve suitable electronics, we designed and built subcellular-sized, wireless, photovoltaic electronic devices that harvest optical energy with high power conversion efficiency. In mice, we demonstrate nonsurgical implantation in an inflamed brain region, as an example of therapeutic target for several neural diseases, by employing monocytes as cells, covalently attaching them to the subcellular-sized, wireless, photovoltaic electronic devices and administering the resulting hybrids intravenously. We also demonstrate neural stimulation with 30-µm precision around the inflamed region. Thus, by fusing electronic functionality with the biological transport and targeting capabilities of living cells, this technology can form the foundation for autonomously implanting bioelectronics.

Monoclonal antibodies (mAbs) are the single largest class of therapeutics used in various indications including oncology, immunology, and neurology. Given their high prevalence, the development of subcutaneously administrable mAb formulations via conventional needles is an urgent and unmet need. Subcutaneous mAb formulations need to meet several stringent requirements, including high concentrations to enable the delivery of therapeutic doses through small volumes, low viscosity to allow self-administration, and high shelf stability, all of which are inherently linked to protein-protein interactions, which have collectively limited mAb concentrations in current commercial formulations to ~150 mg/ml. Here, we report the use of ionic liquids (ILs) to mitigate protein-protein interactions to formulate antibodies at an ultra-high concentration in excess of 200 mg/ml. In addition to solubilizing antibodies at such high concentrations, IgG-IL formulations maintained a viscosity below the injectable threshold of 20 cP, remained stable at even room temperature and 37 °C, and exhibited improved bioavailability compared to saline formulations upon subcutaneous administration.

Macrophages and T cells communicate under homeostatic and pathological conditions. Previous studies elucidated biochemical crosstalk between macrophages and T cells. However, recent technological advances in multiplex tissue imaging reveal that these cells are often located proximally. Notably, recent clinical studies link the proximity of macrophages and T cells to cancer outcomes. These observations suggest that physical contact between the two cell types might influence their phenotype and activity. However, systematic investigations of the potential role of physical contact between these cells are lacking. To address this gap, we developed three-dimensional (3D) coculture assays to study the potential role of physical contact between naïve macrophages and activated CD8 + T cells cultured in 3D Matrigel matrix. Under contact conditions, macrophages and T cells were coencapsulated in the same matrix, whereas under no-contact conditions, they were cultured in matrix, separated by a Transwell membrane. Our findings indicated that T cells changed their migration behavior by stopping and moving over the surface of naïve macrophages during coculture. We quantitatively determined T cells establish durable contact with macrophages, which informed our hypothesis that physical interactions between macrophage-T cells may induce phenotypic changes. Physical contact led to a 3-fold increase in IFN-γ secretion, a key effector molecule of CD8 + T cells. The increase in IFN-γ was mediated by JAK and led to a 2-fold upregulation of ICAM-1 and increased PD-L1 expression. Our findings point to a model whereby activated T cells migrate toward macrophages and are held in proximity by ICAM-1 adhesion molecules, leading to increased production of IFN-γ and PD-L1 expression. These results establish that physical contact is an important determinant of macrophage and T cell states. Broadly, our study establishes a foundation to use biomaterials as a tool to provide mechanistic insights into heterotypic cell interactions to enable rational manipulation of the immune response.

BACKGROUND: Macrophages have been classically associated with their innate immune functions of responding to acute injury or pathogenic insult, but they have been largely overlooked as primary initiators of adaptive immune responses. Here, we demonstrate that adoptively transferred macrophages, with optimal activation prior to administration, act as a potent cellular cancer therapeutic platform against a murine melanoma model. METHOD: The macrophage therapy was prepared from bone marrow-derived macrophages, pretreated ex vivo with an activation cocktail containing interferon-γ, tumor necrosis factor-α, polyinosinic:polycytidylic acid, and anti-CD40 antibody. The therapy was administered to tumor-bearing mice via the tail vein. Tumor growth and survival of the treated mice were monitored to evaluate therapeutic efficacy. Tumors and spleens were processed to examine immune responses and underlying mechanisms. RESULTS: This immunotherapy platform elicits systemic immune responses while infiltrating the tumor to exert direct antitumor effects in support of the systemic adaptive response. The macrophage-based immunotherapy produced a strong CD8+T cell response along with robust natural killer and CD4+T cell activation, inducing a "hot" tumor transition and achieving effective tumor suppression. CONCLUSIONS: Owing to their inherent ability to home to and infiltrate inflamed tissues, macrophage-based cancer immunotherapies exhibited a unique in vivo trafficking behavior, efficiently reaching and persisting within tumors. Macrophages orchestrated a multiarmed immune attack led by CD8+T cells, with the potential for local, intratumoral activation of effector cells, demonstrating a novel cancer immunotherapy platform with meaningfully different characteristics than clinically evaluated alternatives.

Malignant brain tumors, particularly glioblastoma multiforme (GBM), are aggressive and fatal cancers. The clinical efficacy of current standard-of-care treatments against brain tumors has been minimal, with no significant improvement over the past 30 years. Driven by the success of chimeric antigen receptor (CAR)-T cells in the clinic for treating certain types of cancer, adoptive cell therapies have been of interest as a hopeful therapeutic modality for brain tumors. Clinical trials of GBM-targeting cell therapies, including CAR-T cells, have been initiated; however, none of them have been approved yet, and new challenges have emerged from the completed clinical trials. These issues are being addressed in ongoing clinical trials and recent preclinical research efforts. Herein, we present an overview of the clinical landscape of cell therapies against brain tumors. We analyze past and active 203 clinical trials focusing on cell therapies for brain tumors, discuss limitations for their clinical translation, and highlight emerging approaches to address these challenges. In addition, we review select preclinical studies that show promise to improve the therapeutic efficacy of therapeutic cells on brain tumors and discuss future prospects.

Abstract Managing delivery of complex multidrug infusions in anesthesia and critical care presents a significant clinical challenge. Current practices relying on manual control of infusion pumps often result in unpredictable drug delivery profiles and dosing errors—key issues highlighted by the United States Food and Drug Administration (FDA). To address these issues, we introduce the SMART (synchronized‐pump management algorithms for reliable therapies) framework, a novel approach that leverages low Reynolds number drug transport physics and machine learning to accurately manage multidrug infusions in real‐time. SMART is activated based on the Shafer number (), a novel non‐dimensional number that quantifies the relative magnitude of a drug's therapeutic action timescale to its transport timescale within infusion manifolds. SMART is useful when , where drug transport becomes the rate limiting step in achieving the desired therapeutic effects. When activated, SMART monitors multidrug concentrations within infusion manifolds and leverages this information to perform end‐to‐end management of drug delivery using an ensemble of deterministic and deep reinforcement learning (RL) decision networks. Notably, SMART RL networks employ differentially sampled split buffer architecture that accelerates learning and improves performance by seamlessly combining deterministic predictions with RL experience during training. SMART deployed in standalone infusion pumps under simulated clinical conditions outperformed state‐of‐the‐art manual control protocols. This framework has the potential to revolutionize critical care by enhancing accuracy of medication delivery and reducing cognitive workloads. Beyond critical care, the ability to accurately manage multi‐liquid delivery via complex manifolds will have important bearings for manufacturing and process control.

Stem cell therapies have emerged as a transformative approach in modern medicine, with the potential to address and possibly cure a broad spectrum of diseases. These therapies utilize living stem cells that can perform complex biological functions not replicable by traditional drugs. Stem cell therapies have an expanding therapeutic landscape, with several products already approved and numerous clinical trials underway. Among the various stem cell types, hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) are most widely studied. In this review, we provide a detailed analysis of the current clinical landscape of stem cell therapies. We review 27 stem cell products that have received regulatory approvals and discuss 800 ongoing clinical trials, with a focus on HSCs and MSCs. We also discuss the critical challenges to be addressed to facilitate the clinical translation of stem cell therapies.

Despite the success of global vaccination campaigns, vaccine access in low-resource settings is an ongoing challenge. Subunit vaccines are a well-established and clinically scalable intervention, yet they have achieved limited success for poorly immunogenic antigens such as those associated with SARS-CoV-2. Delivery strategies that promote gradual release of subunit vaccines from the injection site offer the potential to improve humoral immunity by enhancing lymph node exposure, however, clinical implementation of this strategy is challenging due to poor scalability and high costs. Here, we propose an approach that uses the polyphenol tannic acid (TA) as a simple and inexpensive strategy to enhance tissue residence of vaccines and subsequent humoral immunity. We show that TA mediates supramolecular interactions between vaccine components and tissue at the subcutaneous injection site to promote extended retention of protein antigens for over one week. In addition to enhancing the magnitude and duration of vaccine drainage to the lymph nodes, inclusion of TA improved accumulation of activated, antigen-laden monocyte-derived dendritic cells (moDCs), promoting long-lasting humoral immunity against the receptor-binding domain (RBD) of SARS-CoV-2 and variants of concern. This system, termed TAPER (Tannic Acid-Promoted Enhanced Retention) provides various translational advantages including one-pot synthesis, scalability, low cost, and modularity, towards realization of effective and accessible subunit vaccines.

No one can predict the future, but that is not going to stop us from taking a shot at it. At BioTM, we do wonder what the future holds for our key scientific areas, including drug delivery, tissue engineering, cell therapy, and biosensors, among many others

Cell immunotherapy is a promising therapeutic modality to combat unmet medical needs. Macrophages offer a prominent cell therapy modality since their phenotypic plasticity allows them to perform a variety of roles including defending against pathogens, inducing/suppressing adaptive immunity, and aiding in wound healing. At the same time, this plasticity is a major hurdle in implementation of macrophage therapy. This hurdle can be overcome by cellular backpacks (BPs), discoidal particles that adhere on the macrophage surface and regulate M1/M2 phenotypic shift in an environment-independent manner. In this study, we engineered IL-4 BPs for maintaining macrophages in the M2 phenotype to regulate excess inflammation in periodontitis, a major oral infectious disease. IL-4 BPs induced and maintained M2 phenotype in macrophages in vitro for several days. After injection of macrophages carrying IL-4 BPs into the gingiva, the cells stayed in the tissue for over 5 days and maintained the M2 phenotype in the disease sites. Furthermore, treatment with IL-4 BP-macrophages significantly suppressed the disease progression. Altogether, a treatment with BP-carrying macrophages offers a promising local therapy against periodontitis.

Vaccination is an important strategy for the prevention of infectious diseases worldwide. Adjuvants can be incorporated in vaccine formulations to enhance the resultant immune response and subsequently confer more robust protection upon natural infection. While adjuvants have exciting potential to improve vaccination, the landscape of materials employed in clinical adjuvants is small and its expansion is needed to facilitate vaccine development against current and future infectious diseases. This study introduces the first ionic liquid (IL) adjuvant comprised of choline and sorbic acid (ChoSorb) to produce an antigen-specific cellular as well as humoral immune response against multiple antigens. The abilities of ChoSorb as a vaccine adjuvant is evaluated and characterized through material analysis, innate immune responses, and adaptive responses to both a model and clinical grade antigen. With the robust immune responses generated by ChoSorb and the accompanying mechanistic insights, this study introduces ILs as a new class of adjuvant materials for future vaccine design.

Immune checkpoint inhibitors (ICIs) represent new therapeutic candidates against glioblastoma multiforme (GBM); however, their efficacy is clinically limited due to both local and systemic immunosuppressive environments. Hence, therapeutic approaches that stimulate local and systemic immune environments can improve the efficacy of ICIs. Here, we report an adoptive cell therapy employing neutrophils (NE) that are activated via surface attachment of drug-free disk-shaped backpacks, termed Cyto-Adhesive Micro-Patches (CAMPs) for treating GBM. CAMP-adhered neutrophils (NE/CAMPs) significantly improved the efficacy of an anti-PD1 antibody (aPD-1) in a subcutaneous murine GBM model (GL261). A combination of NE/CAMPs and aPD-1 completely regressed subcutaneous GL261 tumors in mice. The efficacy of NE/CAMPs against GBM was also tested in an orthotopic GL261 model. Neutrophil's ability to migrate into the brain was not affected by CAMP attachment, and intracerebral NE/CAMP accumulation was observed in mice-bearing orthotopic GBM. The combination treatment of NE/CAMPs and aPD-1 activated systemic immune responses mediated by T cells and showed improved therapeutic responses compared with aPD-1 alone in the orthotopic GBM model. These results suggest that immunomodulation with NE/CAMPs offers a potential approach for the treatment of GBM by combination with ICIs.

Cell therapies are at the forefront of novel therapeutics. Neutrophils, despite being the most populous immune cells in human blood circulation, are not considered a viable option for cellular therapies because of their short lifespan and poor understanding of their role in the pathophysiology of various diseases. In inflammatory conditions, neutrophils exhibit an activated phenotype. Activation brings about significant changes to neutrophil biology such as increased lifespan, inflammatory cytokine secretion, and enhanced effector functions. Activated neutrophils also possess the potential to stimulate the downstream immune response and are described as essential effectors in the immune response to tumors. This makes activated neutrophils an interesting candidate for cell therapies. Here, we review the biology of activated neutrophils in detail. We discuss the different ways neutrophils can be activated and the effect they have on other immune cells for stimulation of downstream immune response. We review the conditions where activated neutrophil therapy can be therapeutically beneficial and discuss the challenges associated with their eventual translation. Overall, this review summarizes the current state of understanding of neutrophil-based immunotherapies and their clinical potential.

Periodontitis is a chronic inflammatory disease that causes destruction of the periodontium and eventual tooth loss. The priority in the periodontal treatment is to remove the subgingival biofilm. Chemical removal of biofilms using antimicrobial agents has been applied in clinical practice. However, their clinical effect is still limited because the agents must overcome biofilm's significant drug tolerance, which is primarily caused by the extracellular matrix, a physical barrier that attenuates drug diffusion. This study aimed to study the use of ionic liquids (ILs), a new class of biocompatible materials, for controlling subgingival biofilms because of their excellent permeability. Choline and geranate (CAGE) IL was tested for its highly potent antiseptic behavior and permeability. Antibacterial tests revealed that the significant efficacy of CAGE against periodontopathic microorganisms was derived from their ability to destroy cell membrane, as demonstrated by membrane permeability assay and transmission electron microscopy imaging. Antibiofilm tests using two pathogenic biofilm models revealed that CAGE exerted efficacy against the biofilm-embedded bacteria, conspicuously neutralized the biofilms, and eventually destroyed the biofilm structure. Furthermore, the penetration of CAGE into the biofilm was visually confirmed using confocal laser scanning microscopy. This study highlighted the potential of CAGE as a powerful antibiofilm therapeutic.

Following our call to join in the discussion over the suitability of implementing a reporting checklist for bio–nano papers, the community responds.

Cellular hitchhiking is an emerging strategy for the in vivo control of adoptively transferred immune cells. Hitchhiking approaches are primarily mediated by adhesion of nano and microparticles to the cell membrane, which conveys an ability to modulate transferred cells via local drug delivery. Although T cell therapies employing this strategy have progressed into the clinic, phagocytic cells including dendritic cells (DCs) are much more challenging to engineer. DC vaccines hold great potential for a spectrum of diseases, and the combination drug delivery is an attractive strategy to manipulate their function and overcome in vivo plasticity. However, DCs are not compatible with current hitchhiking approaches due to their broad phagocytic capacity. In this work, we developed and validated META (membrane engineering using tannic acid) to enable DC cellular hitchhiking for the first time. META employs the polyphenol tannic acid (TA) to facilitate supramolecular assembly of protein drug cargoes on the cell membrane, enabling the creation of cell surface-bound formulations for local drug delivery to carrier DCs. We optimized META formulations to incorporate and release protein cargoes with varying physical properties alone and in combination and to preserve DC viability and critical functions such as migration. We further show that META loaded with either a pro- or anti-inflammatory cargo can influence the carrier cell phenotype, thus demonstrating the flexibility of the approach for applications from cancer to autoimmune disease. Overall, this approach illustrates a new platform for the local control of phagocytic immune cells as a next step to advance DC therapies in the clinic.

B cells, despite their several unique functionalities, remain largely untapped for use as an adoptive cell therapy and are limited to in vitro use for antibody production. B cells can be easily sourced, they possess excellent lymphoid-homing capabilities, and they can act as antigen-presenting cells (APCs), offering an alternative to dendritic cells (DCs), which have shown limited efficacy in the clinical setting. Soluble factors such as IL-4 and anti-CD40 antibody can enhance the activation, survival, and antigen-presenting capabilities of B cells; however, it is difficult to attain sufficiently high concentrations of these biologics to stimulate B cells in vivo . Micropatches as Cell Engagers (MACE) are polymeric microparticles, surface functionalized with anti-CD40 and anti-IgM, which can attach to B cells and simultaneously engage multiple B-cell receptors (BCR) and CD40 receptors. Stimulation of these receptors through MACE, unlike free antibodies, enhanced the display of costimulatory molecules on the B-cell surface, increased B-cell viability, and improved antigen presentation by B cells to T cells in vitro . B-cell activation by MACE further synergized with soluble IL-4 and anti-CD40. MACE also elicited T-cell chemokine secretion by B cells. Upon intravenous adoptive transfer, MACE-bound B cells homed to the spleen and lymph nodes, key sites for antigen presentation to T cells. Adoptive transfer of MACE-B cells pulsed with the CD4+ and CD8+ epitopes of ovalbumin significantly delayed tumor progression in a murine subcutaneous EG7-OVA tumor model, demonstrating the functional benefit conferred to B cells by MACE.

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.

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.

Messenger ribonucleic acid (mRNA) has long been touted as a next-generation therapeutic modality for infectious disease, cancer, and genetic disorders. Lipid nanoparticles (LNPs) provide an elegant delivery strategy for mRNA cargo to help realize this potential for vaccination. However, systemic exposure seen with traditional LNP formulations can have significant implications on efficacy and safety. Efforts to mitigate this have largely been focused on laborious lipid or LNP redesign. Here, the use of a deep eutectic-lipid nanocomposite delivery system for the tuning of mRNA expression for intramuscular injections in vivo is reported. One deep eutectic, cholinium malonate, allows for the linear control of percent expression at the muscular injection site based solely on its concentration in the formulation. The same deep eutectic solvent (DES) can increase local muscle expression by 68% and significantly decrease off-target liver expression by 72%. Physico-chemical studies suggest that the DES incorporates into or onto the pre-formed LNPs thus impacting endosomal escape and in situ interactions. These nanocomposites provide new possibilities for previously approved LNP formulations and without the need for lipid redesign to induce localized expression.

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.

Adoptive cell therapies are dramatically altering the treatment landscape of cancer. However, treatment of solid tumors remains a major unmet need, in part due to limited adoptive cell infiltration into the tumor and in part due to the immunosuppressive tumor microenvironment. The heterogeneity of tumors and presence of nonresponders also call for development of antigen-independent therapeutic approaches. Myeloid cells offer such an opportunity, given their large presence in the immunosuppressive tumor microenvironment, such as in triple negative breast cancer. However, their therapeutic utility is hindered by their phenotypic plasticity. Here, the impressive trafficking ability of adoptively transferred monocytes is leveraged into the immunosuppressive 4T1 tumor to develop an antitumor therapy. To control monocyte differentiation in the tumor microenvironment, surface-adherent "backpacks" stably modified with interferon gamma (IFNγ) are developed to stimulate macrophage plasticity into a pro-inflammatory, antitumor phenotype, a strategy as referred to as Ornate Polymer backpacks on Tissue Infiltrating Monocytes (OPTIMs). Treatment with OPTIMs substantially reduces tumor burden in a mouse 4T1 model and significantly increases survival. Cytokine and immune cell profiling reveal that OPTIMs remodeled the tumor microenvironment into a pro-inflammatory state.

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.

Systemic drug delivery is the current clinically preferred route for cancer therapy. However, challenges associated with tumor localization and off-tumor toxic effects limit the clinical effectiveness of this route. Locoregional drug delivery is an emerging viable alternative to systemic therapies. With the improvement in real-time imaging technologies and tools for direct access to tumor lesions, the clinical applicability of locoregional drug delivery is becoming more prominent. Theoretically, locoregional treatments can bypass challenges faced by systemic drug delivery. Preclinically, locoregional delivery of drugs has demonstrated enhanced therapeutic efficacy with limited off-target effects while still yielding an abscopal effect. Clinically, an array of locoregional strategies is under investigation for the delivery of drugs ranging in target and size. Locoregional tumor treatment strategies can be classified into two main categories: 1) direct drug infusion via injection or implanted port and 2) extended drug elution via injected or implanted depot. The number of studies investigating locoregional drug delivery strategies for cancer treatment is rising exponentially, in both preclinical and clinical settings, with some approaches approved for clinical use. Here, we highlight key preclinical advances and the clinical relevance of such locoregional delivery strategies in the treatment of cancer. Furthermore, we critically analyze 949 clinical trials involving locoregional drug delivery and discuss emerging trends.

Abstract Not Provided

The choroid plexus (ChP) of the brain plays a central role in orchestrating the recruitment of peripheral leukocytes into the central nervous system (CNS) through the blood-cerebrospinal fluid (BCSF) barrier in pathological conditions, thus offering a unique niche to diagnose CNS disorders. We explored whether magnetic resonance imaging of the ChP could be optimized for mild traumatic brain injury (mTBI). mTBI induces subtle, yet influential, changes in the brain and is currently severely underdiagnosed. We hypothesized that mTBI induces sufficient alterations in the ChP to cause infiltration of circulating leukocytes through the BCSF barrier and developed macrophage-adhering gadolinium [Gd(III)]-loaded anisotropic micropatches (GLAMs), specifically designed to image infiltrating immune cells. GLAMs are hydrogel-based discoidal microparticles that adhere to macrophages without phagocytosis. We present a fabrication process to prepare GLAMs at scale and demonstrate their loading with Gd(III) at high relaxivities, a key indicator of their effectiveness in enhancing image contrast and clarity in medical imaging. In vitro experiments with primary murine and porcine macrophages demonstrated that GLAMs adhere to macrophages also under shear stress and did not affect macrophage viability or functions. Studies in a porcine mTBI model confirmed that intravenously administered macrophage-adhering GLAMs provide a differential signal in the ChP and lateral ventricles at Gd(III) doses 500- to 1000-fold lower than those used in the current clinical standard Gadavist. Under the same mTBI conditions, Gadavist did not offer a differential signal at clinically used doses. Our results suggest that macrophage-adhering GLAMs could facilitate mTBI diagnosis.

Traumatic brain injury (TBI) is a debilitating disease with no current therapies outside of acute clinical management. While acute, controlled inflammation is important for debris clearance and regeneration after injury, chronic, rampant inflammation plays a significant adverse role in the pathophysiology of secondary brain injury. Immune cell therapies hold unique therapeutic potential for inflammation modulation, due to their active sensing and migration abilities. Macrophages are particularly suited for this task, given the role of macrophages and microglia in the dysregulated inflammatory response after TBI. However, maintaining adoptively transferred macrophages in an anti-inflammatory, wound-healing phenotype against the proinflammatory TBI milieu is essential. To achieve this, we developed discoidal microparticles, termed backpacks, encapsulating anti-inflammatory interleukin-4, and dexamethasone for ex vivo macrophage attachment. Backpacks durably adhered to the surface of macrophages without internalization and maintained an anti-inflammatory phenotype of the carrier macrophage through 7 days in vitro. Backpack-macrophage therapy was scaled up and safely infused into piglets in a cortical impact TBI model. Backpack-macrophages migrated to the brain lesion site and reduced proinflammatory activation of microglia in the lesion penumbra of the rostral gyrus of the cortex and decreased serum concentrations of proinflammatory biomarkers. These immunomodulatory effects elicited a 56% decrease in lesion volume. The results reported here demonstrate, to the best of our knowledge, a potential use of a cell therapy intervention for a large animal model of TBI and highlight the potential of macrophage-based therapy. Further investigation is required to elucidate the neuroprotection mechanisms associated with anti-inflammatory macrophage therapy.

Microbubbles (MB) are widely used for ultrasound (US) imaging and drug delivery. MB are typically spherically shaped, due to surface tension. When heated above their glass transition temperature, polymer-based MB can be mechanically stretched to obtain an anisotropic shape, endowing them with unique features for US-mediated blood-brain barrier (BBB) permeation. It is here shown that nonspherical MB can be surface-modified with BBB-specific targeting ligands, thereby promoting binding to and sonopermeation of blood vessels in the brain. Actively targeted rod-shaped MB are generated via 1D stretching of spherical poly(butyl cyanoacrylate) MB and via subsequently functionalizing their shell with antitransferrin receptor (TfR) antibodies. Using US and optical imaging, it is demonstrated that nonspherical anti-TfR-MB bind more efficiently to BBB endothelium than spherical anti-TfR-MB, both in vitro and in vivo. BBB-associated anisotropic MB produce stronger cavitation signals and markedly enhance BBB permeation and delivery of a model drug as compared to spherical BBB-targeted MB. These findings exemplify the potential of antibody-modified nonspherical MB for targeted and triggered drug delivery to the brain.

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.

Long-term remission in cancer patients treated with ex vivo bona fide M1-induced macrophages has been poor, and the reasons behind this are not understood. Injected M1 macrophages must physically migrate to tumors to execute their role that leads to a therapeutic benefit. However, the trafficking of macrophages to tumors has not been rigorously studied. We hypothesized that trafficking capabilities of macrophages are impacted when naïve M0 macrophages are converted into an M1 phenotype for macrophage therapy. To test this, we developed a three-dimensional assay comprising a tumor spheroid and macrophages to quantify macrophage tumor transport. Cell migration, permeability, and kinetics of tumor entry were quantitatively defined and compared between macrophage phenotypes. Our results demonstrate that compared to M0 macrophages, M1 macrophages migrate less efficiently toward the tumor spheroid and exhibit a fivefold lower tumor permeability. Live imaging data combined with unsupervised machine learning algorithms reveal that macrophage migration correlates with their shape transitions. Our studies highlight the importance of transport considerations in determining the efficacy of cell therapies. This study quantitatively demonstrates that the transport properties of macrophages in tumors depend on their phenotype.