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.

MMP-responsive transformation nanomaterials with IAP antagonist to boost immune checkpoint therapy.

The clinical effect of immune checkpoint therapy is limited by the poor blocking efficiency of immune checkpoints and the insufficient infiltration of tumor-specific T cells. Here, we constructed enzyme-responsive PVA-peptide conjugates (PPCs) to achieve re-assembly with enhanced accumulation in the tumor region, enable enhanced PD-L1 occupancy and improve the blocking efficiency. The self-assembled PPC-1 nanoparticles can enter tumor environment, whereas the enzyme-cleavable peptide was digested under overgenerated matrix metalloproteinases (MMP). The accumulated PPC-1 simultaneously transformed into ß-sheet fibrous structures around the solid tumor and remained stable for over 96 h, which led to efficiently interrupting the PD-1/PD-L1 interaction. Upon introduction of the IAP antagonists, the non-classical NF-κB pathway of dendritic cells was activated and increased the infiltration of T cells in tumors. With the synergistic contribution of IAP antagonists from the substantial increase in expression of chemokines (CCL5 and CXCL9) and adequate T-cell infiltration in tumor sites, PPC-1 improved the biodistribution and accumulation of PD-L1 antagonists in tumor regions ultimately realizing higher-performance (P < 0.01) tumor growth inhibition efficiency (~80%) than PPC-2 group (~58%) in B16F10 tumor-bearing mice. The growth of the second tumor at the distal end was obviously inhibited (P < 0.01) after the resection of the primary tumor. The combined efficacy was similar to that observed in a Pan02 pancreatic cancer tumor model. This strategy aims to offer novel perspective for the development of locational assembly platforms in vivo and the optimal design of immune checkpoint combination therapy.

Hypoxia-modulatory nanomaterials to relieve tumor hypoxic microenvironment and enhance immunotherapy: Where do we stand?

The past several years have witnessed the blooming of emerging immunotherapy, as well as their therapeutic potential in remodeling the immune system. Nevertheless, with the development of biological mechanisms in oncology, it has been demonstrated that hypoxic tumor microenvironment (TME) seriously impairs the therapeutic outcomes of immunotherapy. Hypoxia, caused by Warburg effect and insufficient oxygen delivery, has been considered as a primary construction element of TME and drawn tremendous attention in cancer therapy. Multiple hypoxia-modulatory theranostic agents have been facing many obstacles and challenges while offering initial therapeutic effect. Inspired by versatile nanomaterials, great efforts have been devoted to design hypoxia-based nanoplatforms to preserve drug activity, reduce systemic toxicity, provide adequate oxygenation, and eventually ameliorate hypoxic-tumor management. Besides these, recently, some curative and innovative hypoxia-related nanoplatforms have been applied in synergistic immunotherapy, especially in combination with immune checkpoint blockade (ICB), immunomodulatory therapeutics, cancer vaccine therapy and immunogenic cell death (ICD) effect. Herein, the paramount impact of hypoxia on tumor immune escape was initially described and discussed, followed by a comprehensive overview on the design tactics of multimodal nanoplatforms based on hypoxia-enabled theranostic agents. A variety of nanocarriers for relieving tumor hypoxic microenvironment were also summarized. On this basis, we presented the latest progress in the use of hypoxia-modulatory nanomaterials for synergistic immunotherapy and highlighted current challenges and plausible promises in this area in the near future. STATEMENT OF SIGNIFICANCE: Cancer immunotherapy, emerging as a novel treatment to eradicate malignant tumors, has achieved a measure of success in clinical popularity and transition. However, over the last decades, hypoxia-induced tumor immune escape has attracted enormous attention in cancer treatment. Limitations of free targeting agents have paved the path for the development of multiple nanomaterials with the hope of boosting immunotherapy. In this review, the innovative design tactics and multifunctional nanocarriers for hypoxia alleviation are summarized, and the smart nanomaterial-assisted hypoxia-modulatory therapeutics for synergistic immunotherapy and versatile biomedical applications are especially highlighted. In addition, the challenges and prospects of clinical transformation are further discussed.

Nanosystems as curative platforms for allergic disorder management.

Allergy, IgE-mediated inflammatory disorders including allergic rhinitis, asthma, and conjunctivitis, affects billions of people worldwide. Conventional means of allergy management include allergen avoidance, pharmacotherapy, and emerging therapies. Among them, chemotherapeutant intake via oral, intravenous, and intranasal routes is always the most common mean. Although current pharmacotherapy exhibit splendid anti-allergic effects, short in situ retention, low bioavailability, and systemic side effects are inevitable. Nowadays, nanoplatforms have provided alternative therapeutic options to obviate the existing weakness via enhancing the solubility of hydrophobic therapeutic agents, achieving in situ drug accumulation, exhibiting controlled and long-time drug release at lesion areas, and providing multi-functional therapeutic strategies. Herein, we highlight the clinical therapeutic strategies and deal with characteristics of the nanoplatform design in allergy interventions via intratracheal, gastrointestinal, intravenous, and ocular paths. The promising therapeutic utilization in a variety of allergic disorders is discussed, and recent perspectives on the feasible advances of nanoplatforms in allergy management are also exploited.