Intranasal Morphology Transformation Nanomedicines for Long-Term Intervention of Allergic Rhinitis.

Intranasal administration has been widely explored as a potential treatment for allergic rhinitis, and improving intranasal penetration and retention of drugs is a challenging requirement to further improve efficacy. Delivery strategies of nanocarriers that enhance mucosal adhesion or mucus penetration have been proposed to improve nasal drug delivery; however, delivery efficiency remains limited by excessive pulmonary deposition and nonspecific cell phagocytosis. In this work, a "nasal in situ assembly" strategy was presented to construct intranasal morphology transformation nanomedicines with enhanced effective drug concentration for long-term intervention of allergic rhinitis. The polymer-polypeptide nanomedicine (PHCK) with a CCR3 antagonistic peptide (C) and a pH-responsive polyethylene glycol (H) was developed, encapsulating ketotifen (KT). PHCK nanoparticles displayed nasal mucosa permeability and transformed to nanofibers in the acidic environment of the nasal cavity, realizing responsive burst release of KT simultaneously. The fibrotic reassembly reduced the cellular internalization of nanomedicine and increased the CCR3 blockade on the eosinophil (EOS) membranes. Both in vitro and in vivo data indicated that PHCK achieved improved drug accumulation and retention in the nasal cavity and decreased pulmonary deposition, then effectively inhibited mast cell degranulation and EOS chemotaxis. This study demonstrates that the "nasal in situ assembly" strategy can improve drug delivery efficiency upon nasal responsive morphologic transformation, providing exploratory perspectives for nasal delivery platforms establishment and boosting therapeutic effect of allergic rhinitis.

Biomimetic nanoparticles for DC vaccination: a versatile approach to boost cancer immunotherapy.

Cancer immunotherapy, which harnesses the immune system to fight cancer, has begun to make a breakthrough in clinical applications. Dendritic cells (DCs) are the bridge linking innate and adaptive immunity and the trigger of tumor immune response. Considering the cumbersome process and poor efficacy of classic DC vaccines, there has been interest in transferring the field of in vitro-generated DC vaccines to nanovaccines. Conventional nanoparticles have insufficient targeting ability and are easily cleared by the reticuloendothelial system. Biological components have evolved very specific functions, which are difficult to fully reproduce with synthetic materials, making people interested in using the further understanding of biological systems to prepare nanoparticles with new and enhanced functions. Biomimetic nanoparticles are semi-biological or nature-derived delivery systems comprising one or more natural materials, which have a long circulation time in vivo and excellent performance of targeting DCs, and can mimic the antigen-presenting behavior of DCs. In this review, we introduce the classification, design, preparation, and challenges of different biomimetic nanoparticles, and discuss their application in activating DCs in vivo and stimulating T cell antitumor immunity. Incorporating biomimetic nanoparticles into cancer immunotherapy has shown outstanding advantages in precisely coaxing the immune system against cancer.

Bridging nanoplatform and vaccine delivery, a landscape of strategy to enhance nasal immunity.

Vaccination is an urgently needed and effective option to address epidemic, cancers, allergies, and other diseases. Nasal administration of vaccines offers many benefits over needle-based injection including high compliance and less risk of infection. Inactivated or attenuated vaccines as convention vaccine present potential risks of pathogenic virulence reversal, the focus of nasal vaccine development has shifted to the use of next-generation (subunit and nucleic acid) vaccines. However, subunit and nucleic acid vaccine intranasally have numerous challenges in development and utilization due to mucociliary clearance, mucosal epithelial tight junction, and enzyme/pH degradation. Nanoplatforms as ideal delivery systems, with the ability to enhance the retention, penetration, and uptake of nasal mucosa, shows great potential in improving immunogenic efficacy of nasal vaccine. This review provides an overview of delivery strategies for overcoming nasal barrier, including mucosal adhesion, mucus penetration, targeting of antigen presenting cells (APCs), enhancement of paracellular transportation. We discuss methods of enhancing antigen immunogenicity by nanoplatforms as immune-modulators or multi-antigen co-delivery. Meanwhile, we describe the application status and development prospect of nanoplatforms for nasal vaccine administration. Development of nanoplatforms for vaccine delivery via nasal route will facilitate large-scale and faster global vaccination, helping to address the threat of epidemics.

Reshaping hypoxia and silencing CD73 via biomimetic gelatin nanotherapeutics to boost immunotherapy.

The ubiquitous hypoxic microenvironment at the tumor site helps to regulate hypoxic inducible factor (HIF-1α), up-regulate downstream CD73-adenosine (CD73-ADO) pathways, and further result in effector T cell function exhaustion, which is regarded as a crucial adverse factor in the poor clinical efficacy of immune checkpoint blockade therapy (ICB). How to reshape hypoxic microenvironment and silence CD73 remains a huge challenge to improve ICB therapeutic outcomes. In this study, cancer cell membrane-camouflaged gelatin nanoparticles (CSG@B16F10) were designed to co-deliver oxygen-generating agent catalase (CAT) and CD73siRNA, thus enhancing tumor oxygenation and alleviating CD73-ADO pathway-mediated T cell immunosuppression. The fabricated biomimetic nanoparticles could efficiently achieve immune evading and homologous targeting by virtue of the retention of cancer cell membrane protein. Matrix metalloproteinases (MMP)-responsive gelatin nanoparticles were gradually disintegrated to accelerate the release of payloads. Rapidly released CAT was found to relieve tumor hypoxia by generating endogenous oxygen, while CD73siRNA effectively silenced target gene, synergically inhibiting CD73 protein expression and facilitating T-cell-specific immunity. Upon introduction of CSG@B16F10 in melanoma-bearing mice, PD-L1 checkpoint blockade achieved optimal tumor suppression (∼83%). The enhanced immune efficacy was mainly manifested by enhanced cytotoxic T cell (CTL), reduced regulatory T cells (Tregs), and increased anti-tumor cytokine secretion. This work presents a new paradigm for the ideal design of biomimetic nanoplatforms and the synergistic treatment of hypoxia alleviation and CD73 silence, greatly promising for enhancing clinical immune potency of PD-1/PD-L1 immune checkpoint blockade.

Bridging micro/nano-platform and airway allergy intervention.

Allergic airway diseases, with incidence augmenting visibly as industrial development and environmental degradation, are characterized by sneezing, itching, wheezing, chest tightness, airway obstruction, and hyperresponsiveness. Current medical modalities attempt to combat these symptoms mostly by small molecule chemotherapeutants, such as corticosteroids, antihistamines, etc., via intranasal approach which is one of the most noninvasive, rapid-absorbed, and patient-friendly routes. Nevertheless, inherent defects for irritation to respiratory mucosa, drug inactivation and degradation, and rapid drug dispersal to off-target sites are inevitable. Lately, intratracheal micro/nano therapeutic systems are emerging as innovative alternatives for airway allergy interventions. This overview introduces several potential application directions of mic/nano-platform in the treatment of airway allergic diseases, including carriers, therapeutic agents, and immunomodulators. The improvement of the existing drug therapy of respiratory allergy management by micro/nano-platform is described in detail. The challenges of the micro/nano-platform nasal approach in the treatment of airway allergy are summarized and the development of micro/nano-platform is also prospected. Although still a burgeoning area, micro/nano therapeutic systems are gradually turning to be realistic orientations as crucial future alternative therapeutic options in allergic airway inflammation interventions.