Onion-like Multifunctional Microtrap Vehicles for Attraction-Trapping-Destruction of Biological Threats.

A multifunctional motile microtrap is developed that is capable of autonomously attracting, trapping, and destroying pathogens by controlled chemoattractant and therapeutic agent release. The onion-inspired multi-layer structure contains a magnesium engine core and inner chemoattractant and therapeutic layers. Upon chemical propulsion, the magnesium core is depleted, resulting in a hollow structure that exposes the inner layers and serves as structural trap. The sequential dissolution and autonomous release of the chemoattractant and killing agents result in long-range chemotactic attraction, trapping, and destruction of motile pathogens. The dissolved chemoattractant (l-serine) significantly increases the accumulation and capture of motile pathogens (E. coli) within the microtrap structure, while the internal release of silver ions (Ag+ ) leads to lysis of the pathogen accumulated within the microtrap cavity.

Nanoparticle-neutrophils interactions for autoimmune regulation.

Neutrophils play an essential role as 'first responders' in the immune response, necessitating many immune-modulating capabilities. Chronic, unresolved inflammation is heavily implicated in the progression and tissue-degrading effects of autoimmune disease. Neutrophils modulate disease pathogenesis by interacting with the inflammatory and autoreactive cells through effector functions, including signaling, degranulation, and neutrophil extracellular traps (NETs) release. Since the current gold standard systemic glucocorticoid administration has many drawbacks and side effects, targeting neutrophils in autoimmunity provides a new approach to developing therapeutics. Nanoparticles enable targeting of specific cell types and controlled release of a loaded drug cargo. Thus, leveraging nanoparticle properties and interactions with neutrophils provides an exciting new direction toward novel therapies for autoimmune diseases. Additionally, recent work has utilized neutrophil properties to design novel targeted particles for delivery into previously inaccessible areas. Here, we outline nanoparticle-based strategies to modulate neutrophil activity in autoimmunity, including various nanoparticle formulations and neutrophil-derived targeting.

Polymerized Salicylic Acid Microparticles Reduce the Progression and Formation of Human Neutrophil Extracellular Traps (NET)s.

Neutrophils can contribute to inflammatory disease propagation via innate mechanisms intended for inflammation resolution. For example, neutrophil extracellular traps (NETs) are necessary for trapping pathogens but can contribute to clot formation and blood flow restriction, that is, ischemia. Currently, no therapeutics in the clinic directly target NETs despite the known involvement of NETs contributing to mortality and increased disease severity. Vascular-deployed particle-based therapeutics are a novel and robust alternative to traditional small-molecule drugs by enhancing drug delivery to cells of interest. This work designs a high-throughput assay to investigate the immunomodulatory behavior and functionality of salicylic acid-based polymer-based particle therapeutics against NETosis in human neutrophils. Briefly, this work finds that polymeric composition plays a role, and particle size can also influence rates of NETosis. Salicylate-based polymeric (Poly-SA) particles are found to functionally inhibit NETosis depending on the particle size and concentration exposed to neutrophils. This work demonstrates the high throughput method can help fast-track particle-based therapeutic optimization and design, more efficiently preparing this innovative therapeutics for the clinic.

Microneedle-mediated Intratumoral Delivery of Anti-CTLA-4 Promotes cDC1-dependent Eradication of Oral Squamous Cell Carcinoma with Limited irAEs.

Head and neck squamous cell carcinoma (HNSCC) ranks sixth in cancer incidence worldwide and has a 5-year survival rate of only 63%. Immunotherapies-principally immune checkpoint inhibitors (ICI), such as anti-PD-1 and anti-CTLA-4 antibodies that restore endogenous antitumor T-cell immunity-offer the greatest promise for HNSCC treatment. Anti-PD-1 has been recently approved for first-line treatment of recurrent and metastatic HNSCC; however, less than 20% of patients show clinical benefit and durable responses. In addition, the clinical application of ICI has been limited by immune-related adverse events (irAE) consequent to compromised peripheral immune tolerance. Although irAEs are often reversible, they can become severe, prompting premature therapy termination or becoming life threatening. To address the irAEs inherent to systemic ICI therapy, we developed a novel, local delivery strategy based upon an array of soluble microneedles (MN). Using our recently reported syngeneic, tobacco-signature murine HNSCC model, we found that both systemic and local-MN anti-CTLA-4 therapy lead to >90% tumor response, which is dependent on CD8 T cells and conventional dendritic cell type 1 (cDC1). However, local-MN delivery limited the distribution of anti-CTLA-4 antibody from areas distal to draining lymphatic basins. Employing Foxp3-GFPDTR transgenic mice to interrogate irAEs in vivo, we found that local-MN delivery of anti-CTLA-4 protects animals from irAEs observed with systemic therapy. Taken together, our findings support the exploration of MN-intratumoral ICI delivery as a viable strategy for HNSCC treatment with reduced irAEs, and the opportunity to target cDC1s as part of multimodal treatment options to boost ICI therapy.

Combinatorial microneedle patch with tunable release kinetics and dual fast-deep/sustained release capabilities.

Transdermal microneedle (MN) drug delivery patches, comprising water-soluble polymers, have played an essential role in diverse biomedical applications, but with limited development towards fast deep release or sustained delivery applications. The effectiveness of such MN delivery patches strongly depends on the materials from which they are constructed. Herein, we present a dual-action combinatorial programmable MN patch, comprising of fast and sustained-release MN zones, with tunable release kinetics towards delivering a wide range of therapeutics over different timeframes in single application. We demonstrate the fine tuning of MN materials; the patches can be tailored to deliver a first payload faster and deeper within minutes, while simultaneously delivering a second payload over long times ranging from weeks to months. The active and rapid burst release relies on embedding biodegradable Mg microparticle 'engines' in dissolvable MNs while the sustained release is attributed to biocompatible polymers that allow prolonged release in a controllable tunable manner. In addition, the patches are characterized and optimized for their design, materials and mechanical properties. These studies indicate that such programmable dual-action versatile MN platform is expected to improve therapeutic efficacy and patient compliance, achieving powerful benefits by single patch application at low manufacturing cost.

Built-In Active Microneedle Patch with Enhanced Autonomous Drug Delivery.

The use of microneedles has facilitated the painless localized delivery of drugs across the skin. However, their efficacy has been limited by slow diffusion of molecules and often requires external triggers. Herein, an autonomous and degradable, active microneedle delivery platform is introduced, employing magnesium microparticles loaded within the microneedle patch, as the built-in engine for deeper and faster intradermal payload delivery. The magnesium particles react with the interstitial fluid, leading to an explosive-like rapid production of H2 bubbles, providing the necessary force to breach dermal barriers and enhance payload delivery. The release kinetics of active microneedles is evaluated in vitro by measuring the amount of IgG antibody (as a model drug) that passed through phantom tissue and a pigskin barrier. In vivo experiments using a B16F10 mouse melanoma model demonstrate that the active delivery of anti-CTLA-4 (a checkpoint inhibitor drug) results in greatly enhanced immune response and significantly longer survival. Moreover, spatially resolved zones of active and passive microneedles allow a combinatorial rapid burst response along with slow, sustained release, respectively. Such versatile and effective autonomous dynamic microneedle delivery technology offers considerable promise for a wide range of therapeutic applications, toward a greatly enhanced outcome, convenience, and cost.

Active Microneedle Administration of Plant Virus Nanoparticles for Cancer in situ Vaccination Improves Immunotherapeutic Efficacy.

The solid tumor microenvironment (TME) poses a significant structural and biochemical barrier to immunotherapeutic agents. To address the limitations of tumor penetration and distribution, and to enhance antitumor efficacy of immunotherapeutics, we present here an autonomous active microneedle (MN) system for the direct intratumoral (IT) delivery of a potent immunoadjuvant, cowpea mosaic virus nanoparticles (CPMV) in vivo. In this active delivery system, magnesium (Mg) microparticles embedded into active MNs react with the interstitial fluid in the TME, generating a propulsive force to drive the nanoparticle payload into the tumor. Active delivery of CPMV payload into B16F10 melanomas in vivo demonstrated substantially more pronounced tumor regression and prolonged survival of tumor-bearing mice compared to that of passive MNs and conventional needle injection. Active MN administration of CPMV also enhanced local innate and systemic adaptive antitumor immunity. Our approach represents an elaboration of conventional CPMV in situ vaccination, highlighting substantial immune-mediated antitumor effects and improved therapeutic efficacy that can be achieved through an active and autonomous delivery system-mediated CPMV in situ vaccination.

Cholla cactus frames as lightweight and torsionally tough biological materials.

Biological materials tested in compression, tension, and impact inspire designs for strong and tough materials, but torsion is a relatively neglected loading mode. The wood skeletons of cholla cacti, subject to spartan desert conditions and hurricane force winds, provide a new template for torsionally resilient biological materials. Novel mesostructural characterization methods of laser-scanning and photogrammetry are used alongside traditional optical microscopy, scanning electron microscopy, and micro-computed tomography to identify mechanisms responsible for torsional resistance. These methods, in combination with finite element analysis reveal how cholla meso and macro-porosity and fibril orientation contribute to highly density-efficient mechanical behavior. Selective lignification and macroscopic tubercle pore geometry contribute to density-efficient shear stiffness, while mesoscopic wood fiber straightening, delamination, pore collapse, and fiber pullout provide extrinsic toughening mechanisms. These energy absorbing mechanisms are enabled by the hydrated material level properties. Together, these hierarchical behaviors allow the cholla to far exceed bamboo and trabecular bone in its ability to combine specific torsional stiffness, strength, and toughness. STATEMENT OF SIGNIFICANCE: The Cholla cactus experiences, due to the high velocity desert winds, high torsional loads. Our study has revealed the amazingly ingenious strategy by which the tubular structure containing arrays of voids intermeshed with wood fibers resists these high loads. Deformation is governed by compressive and tensile stresses which are greatest at 45 degrees to the cross section. It proceeds by stretching, sliding, and bending of the wood fibers which are coupled with the pore collapse, resulting in delayed failure and a high torsional toughness.