Uptake of Cyclodextrin Nanoparticles by Macrophages is Dependent on Particle Size and Receptor-Mediated Interactions.

Physiochemical properties of nanoparticles, such as their size and chemical composition, dictate their interaction with professional phagocytes of the innate immune system. Macrophages, in particular, are key regulators of the immune microenvironment that heavily influence particle biodistribution as a result of their uptake. This attribute enables macrophage-targeted delivery, including for phenotypic modulation. Saccharide-based materials, including polyglucose polymers and nanoparticles, are efficient vehicles for macrophage-targeted delivery. Here, we investigate the influence of particle size on cyclodextrin nanoparticle (CDNP) uptake by macrophages and further examine the receptor-mediated interactions that drive macrophage-targeted delivery. We designed and synthesized CDNPs ranging in size from 25 nm to >100 nm in diameter. Increasing particle size was correlated with greater uptake by macrophages in vitro. Both scavenger receptor A1 and mannose receptor were critical mediators of macrophage-targeted delivery, inhibition of which reduced the extent of uptake. Finally, we investigated the cellular bioavailability of drug-loaded CDNPs using a model anti-inflammatory drug, celastrol, which demonstrated that drug bioactivity is improved by CDNP loading relative to free drug alone. This study thus elucidates the interactions between the polyglucose nanoparticles and macrophages, thereby facilitating their application in macrophage-targeted drug delivery that has applications in the context of tissue injury and repair.

Control of the post-infarct immune microenvironment through biotherapeutic and biomaterial-based approaches.

Ischemic heart failure (IHF) is a leading cause of morbidity and mortality worldwide, for which heart transplantation remains the only definitive treatment. IHF manifests from myocardial infarction (MI) that initiates tissue remodeling processes, mediated by mechanical changes in the tissue (loss of contractility, softening of the myocardium) that are interdependent with cellular mechanisms (cardiomyocyte death, inflammatory response). The early remodeling phase is characterized by robust inflammation that is necessary for tissue debridement and the initiation of repair processes. While later transition toward an immunoregenerative function is desirable, functional reorientation from an inflammatory to reparatory environment is often lacking, trapping the heart in a chronically inflamed state that perpetuates cardiomyocyte death, ventricular dilatation, excess fibrosis, and progressive IHF. Therapies can redirect the immune microenvironment, including biotherapeutic and biomaterial-based approaches. In this review, we outline these existing approaches, with a particular focus on the immunomodulatory effects of therapeutics (small molecule drugs, biomolecules, and cell or cell-derived products). Cardioprotective strategies, often focusing on immunosuppression, have shown promise in pre-clinical and clinical trials. However, immunoregenerative therapies are emerging that often benefit from exacerbating early inflammation. Biomaterials can be used to enhance these therapies as a result of their intrinsic immunomodulatory properties, parallel mechanisms of action (e.g., mechanical restraint), or by enabling cell or tissue-targeted delivery. We further discuss translatability and the continued progress of technologies and procedures that contribute to the bench-to-bedside development of these critically needed treatments.

T cell-independent eradication of experimental glioma by intravenous TLR7/8-agonist-loaded nanoparticles.

Glioblastoma, the most common and aggressive primary brain tumor type, is considered an immunologically "cold" tumor with sparse infiltration by adaptive immune cells. Immunosuppressive tumor-associated myeloid cells are drivers of tumor progression. Therefore, targeting and reprogramming intratumoral myeloid cells is an appealing therapeutic strategy. Here, we investigate a ß-cyclodextrin nanoparticle (CDNP) formulation encapsulating the Toll-like receptor 7 and 8 (TLR7/8) agonist R848 (CDNP-R848) to reprogram myeloid cells in the glioma microenvironment. We show that intravenous monotherapy with CDNP-R848 induces regression of established syngeneic experimental glioma, resulting in increased survival rates compared with unloaded CDNP controls. Mechanistically, CDNP-R848 treatment reshapes the immunosuppressive tumor microenvironment and orchestrates tumor clearing by pro-inflammatory tumor-associated myeloid cells, independently of T cells and NK cells. Using serial magnetic resonance imaging, we identify a radiomic signature in response to CDNP-R848 treatment and ultrasmall superparamagnetic iron oxide (USPIO) imaging reveals that immunosuppressive macrophage recruitment is reduced by CDNP-R848. In conclusion, CDNP-R848 induces tumor regression in experimental glioma by targeting blood-borne macrophages without requiring adaptive immunity.

Sustained release of drug-loaded nanoparticles from injectable hydrogels enables long-term control of macrophage phenotype.

Injectable hydrogels may be pre-formed through dynamic crosslinks, allowing for injection and subsequent retention in the tissue by shear-thinning and self-healing processes, respectively. These properties enable the site-specific delivery of encapsulated therapeutics; yet, the sustained release of small-molecule drugs and their cell-targeted delivery remains challenging due to their rapid diffusive release and non-specific cellular biodistribution. Herein, we develop an injectable hydrogel system composed of a macrophage-targeted nanoparticle (cyclodextrin nanoparticles, CDNPs) crosslinked by adamantane-modified hyaluronic acid (Ad-HA). The polymer-nanoparticle hydrogel uniquely leverages cyclodextrin's interaction with small molecule drugs to create a spatially discrete drug reservoir and with adamantane to yield dynamic, injectable hydrogels. Through an innovative two-step drug screening approach and examination of 45 immunomodulatory drugs with subsequent in-depth transcriptional profiling of both murine and human macrophages, we identify celastrol as a potent inhibitor of pro-inflammatory (M1-like) behavior that furthermore promotes a reparatory (M2-like) phenotype. Celastrol encapsulation within the polymer-nanoparticle hydrogels permitted shear-thinning injection and sustained release of drug-laden nanoparticles that targeted macrophages to modulate cell behavior for greater than two weeks in vitro. The modular hydrogel system is a promising approach to locally modulate cell-specific phenotype in a range of applications for immunoregenerative medicine.

Applications of Macrocyclic Host Molecules in Immune Modulation and Therapeutic Delivery.

The immune system plays a central role in the development and progression of human disease. Modulation of the immune response is therefore a critical therapeutic target that enables us to approach some of the most vexing problems in medicine today such as obesity, cancer, viral infection, and autoimmunity. Methods of manipulating the immune system through therapeutic delivery centralize around two common themes: the local delivery of biomaterials to affect the surrounding tissue or the systemic delivery of soluble material systems, often aided by context-specific cell or tissue targeting strategies. In either case, supramolecular interactions enable control of biomaterial composition, structure, and behavior at the molecular-scale; through rational biomaterial design, the realization of next-generation immunotherapeutics and immunotheranostics is therefore made possible. This brief review highlights methods of harnessing macromolecular interaction for immunotherapeutic applications, with an emphasis on modes of drug delivery.

Polymeric materials for immune engineering: Molecular interaction to biomaterial design.

Biomaterials continue to evolve as complex engineered tools for interactively instructing biological systems, aiding in the understanding and treatment of various disease states through intimate biological interaction. The immune response to polymeric materials is a critical area of study, as it governs the body's response to biomaterial implants, drug delivery vehicles, and even therapeutic drug formulations. Importantly, the development of the immune response to polymeric biomaterials spans length scales - from single molecular interactions to the complex sensing of bulk biophysical properties, all of which coordinate a tissue- and systems-level response. In this review, we specifically discuss a bottom-up approach to designing biomaterials that use molecular-scale interactions to drive immune response to polymers and discuss how these interactions can be leveraged for biomaterial design. STATEMENT OF SIGNIFICANCE: The immune system is an integral controller of (patho)physiological processes, affecting nearly all aspects of human health and disease. Polymeric biomaterials, whether biologically derived or synthetically produced, can potentially alter the behavior of immune cells due to their molecular-scale interaction with individual cells, as well as their interpretation at the bulk scale. This article reviews common mechanisms by which immune cells interact with polymers at the molecular level and discusses how these interactions are being leveraged to produce the next generation of biocompatible and immunomodulatory materials.