The tumour microenvironment thwarts conventional immunotherapy through multiple immunologic mechanisms, such as the secretion of the transforming growth factor-β (TGF-β), which stunts local tumour immune responses. Therefore, high doses of interleukin-2 (IL-2), a conventional cytokine for metastatic melanoma, induces only limited responses. To overcome the immunoinhibitory nature of the tumour microenvironment, we developed nanoscale liposomal polymeric gels (nanolipogels; nLGs) of drug-complexed cyclodextrins and cytokine-encapsulating biodegradable polymers that can deliver small hydrophobic molecular inhibitors and water-soluble protein cytokines in a sustained fashion to the tumour microenvironment. nLGs releasing TGF-β inhibitor and IL-2 significantly delayed tumour growth, increased survival of tumour-bearing mice, and increased the activity of natural killer cells and of intratumoral-activated CD8+ T-cell infiltration. We demonstrate that the efficacy of nLGs in tumour immunotherapy results from a crucial mechanism involving activation of both innate and adaptive immune responses.

We conducted a descriptive time-series study of pediatric emergency healthcare use during the onset of severe acute respiratory syndrome coronavirus 2 pandemic after a statewide stay-at-home order. Our study demonstrated decreased volume, increased acuity, and generally consistent chief complaints compared with the prior 3 years (2017 through 2019). Ingestions became a significantly more common chief complaint in 2020.

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Biodegradable polymeric nanoparticles are widely recognized as efficacious drug delivery vehicles, yet the rational engineering of nanoparticle surfaces in order to improve biodistribution, reduce clearance, and/or improve targeting remains a significant challenge. We have previously demonstrated that an amphiphilic conjugate of avidin and palmitic acid can be used to modify poly(lactic-co-glycolic acid) (PLGA) particle surfaces to display functional avidin groups, allowing for the facile attachment of biotinylated ligands for targeting or steric stabilization. Here, we hypothesized that the incorporation, density, and stability of surface-presented avidin could be modulated through varying the lipophilicity of its fatty acid conjugate partner. We tested this hypothesis by generating a set of novel conjugates incorporating avidin and common fatty acids. We found that conjugation to linoleic acid resulted in a ∼60% increase in the incorporation of avidin on the nanoparticle surface compared to avidin–palmitic acid, which exhibited the highest avidin incorporation in previous studies. Further, the linoleic acid–avidin conjugate yielded nanoparticles with enhanced ability to bind biotinylated ligands compared to the previous method; nanoparticles modified with avidin–linoleic acid bound ∼170% more biotin–HRP than those made with avidin–palmitic acid and ∼1300% more than particles made without conjugated avidin. Most critically, increased ligand density on anti-CD4-targeted nanoparticles formulated with the linoleic acid–avidin conjugate resulted in a 5% increase in binding of CD4+ T cells. Thus we conclude that the novel avidin–linoleic acid conjugate facilitates enhanced ligand density on PLGA nanoparticles, resulting in functional enhancement of cellular targeting.

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