Brain glioma treatment with checkpoint inhibitor antibodies to cytotoxic T-lymphocyteassociated antigen 4 (a-CTLA-4) and programmed cell death-1 (a-PD-1) was largely unsuccessful due to their inability to cross blood-brain barrier (BBB). Here we describe targeted nanoscale immunoconjugates (NICs) on natural biopolymer scaffold, poly(β-L-malic acid), with covalently attached a-CTLA-4 or a-PD-1 for systemic delivery across the BBB and activation of local brain anti-tumor immune response. NIC treatment of mice bearing intracranial GL261 glioblastoma (GBM) results in an increase of CD8+ T cells, NK cells and macrophages with a decrease of regulatory T cells (Tregs) in the brain tumor area. Survival of GBM-bearing mice treated with NIC combination is significantly longer compared to animals treated with single checkpoint inhibitor-bearing NICs or free a-CTLA-4 and a-PD-1. Our study demonstrates trans-BBB delivery of tumor-targeted polymer-conjugated checkpoint inhibitors as an effective GBM treatment via activation of both systemic and local privileged brain tumor immune response.

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Mobile cloud computing (MCC) has recently been drawing increased attention in academia as well as industry. Content retrieval is a critical service, for many mobile cloud applications and in turns relies on other resources and tools, e.g., internal storage, content searching and sharing, etc. Previous studies have shown that conventional ICN interest query schemes and content searching architectures, if not properly designed, can cause significant performance degradation and energy consumption, especially for large scale MANETs.In this paper, we specifically address the scalability and energy efficiency of the content retrieval scheme in mobile cloud computing. We propose a direction-selective forwarding scheme for the content query method that decreases traffic overhead and energy cost caused by duplicate copies of the query packets. We also advocate the parallel search method of multiple caches to increase the hit rate.Simulation experiments show that the proposed scheme yields significant improvements in efficiency and scalability for the content retrieval in large scale MANETs.

Glioblastoma (GBM) is the most prevalent primary brain cancer in the pediatric and adult population. It is known as an untreatable tumor in urgent need of new therapeutic approaches. The objective of this work was to develop multifunctional nanomedicines to treat GBM in clinical practice using combination therapy for several targets. We developed multifunctional nanopolymers (MNPs) based on a naturally derived biopolymer, poly(β-L-malic) acid, which are suitable for central nervous system (CNS) treatment. These MNPs contain several anticancer functional moieties with the capacity of crossing the blood–brain barrier (BBB), targeting GBM cells and suppressing two important molecular markers, tyrosine kinase transmembrane receptors EGFR/EGFRvIII and c-Myc nuclear transcription factor. The reproducible syntheses of MNPs where monoclonal antibodies are replaced with AP-2 peptide for effective BBB delivery were presented. The active anticancer inhibitors of mRNA/protein syntheses were Morpholino antisense oligonucleotides (AONs). Two ways of covalent AON-polymer attachments with and without disulfide bonds were explored. These MNPs bearing AONs to EGFR/EGFRvIII and c-Myc, as well as in a combination with the polymer-attached checkpoint inhibitor anti-PD-1 antibody, orchestrated a multi-pronged attack on intracranial mouse GBM to successfully block tumor growth and significantly increase survival of brain tumor-bearing animals.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20129-9

This Article contained an error in Fig. 1. In figure 1g, the PD-1 antigen, green oval, was incorrectly shown binding to a-msTfR instead of a-PD1. This error has now been corrected in the HTML and PDF versions of the article.

Research has increasingly focused on the delivery of high, often excessive amounts of drugs, neglecting negative aspects of the carrier’s physical preconditions and biocompatibility. Among them, little attention has been paid to “small but beautiful” design of vehicle and multiple cargo to achieve effortless targeted delivery into deep tissue. The design of small biopolymers for deep tissue targeted delivery of multiple imaging agents and therapeutics (mini-nano carriers) emphasizes linear flexible polymer platforms with a hydrodynamic diameter of 4 nm to 10 nm, geometrically favoring dynamic juxtaposition of ligands to host receptors, and economic drug content. Platforms of biodegradable, non-toxic poly(β-l-malic acid) of this size carrying multiple chemically bound, optionally nature-derived or synthetic affinity peptides and drugs for a variety of purposes are described in this review with specific examples. The size, shape, and multiple attachments to membrane sites accelerate vascular escape and fast blood clearance, as well as the increase in medical treatment and contrasts for tissue imaging. High affinity antibodies routinely considered for targeting, such as the brain through the blood–brain barrier (BBB), are replaced by moderate affinity binding peptides (vectors), which penetrate at high influxes not achievable by antibodies.