Enhancing in vivo cell and tissue targeting by modulation of polymer nanoparticles and macrophage decoys.

The in vivo efficacy of polymeric nanoparticles (NPs) is dependent on their pharmacokinetics, including time in circulation and tissue tropism. Here we explore the structure-function relationships guiding physiological fate of a library of poly(amine-co-ester) (PACE) NPs with different compositions and surface properties. We find that circulation half-life as well as tissue and cell-type tropism is dependent on polymer chemistry, vehicle characteristics, dosing, and strategic co-administration of distribution modifiers, suggesting that physiological fate can be optimized by adjusting these parameters. Our high-throughput quantitative microscopy-based platform to measure the concentration of nanomedicines in the blood combined with detailed biodistribution assessments and pharmacokinetic modeling provides valuable insight into the dynamic in vivo behavior of these polymer NPs. Our results suggest that PACE NPs-and perhaps other NPs-can be designed with tunable properties to achieve desired tissue tropism for the in vivo delivery of nucleic acid therapeutics. These findings can guide the rational design of more effective nucleic acid delivery vehicles for in vivo applications.

Biophysical and mechanobiological considerations for T-cell-based immunotherapy.

Immunotherapies modulate the body's defense system to treat cancer. While these therapies have shown efficacy against multiple types of cancer, patient response rates are limited, and the off-target effects can be severe. Typical approaches in developing immunotherapies tend to focus on antigen targeting and molecular signaling, while overlooking biophysical and mechanobiological effects. Immune cells and tumor cells are both responsive to biophysical cues, which are prominent in the tumor microenvironment. Recent studies have shown that mechanosensing - including through Piezo1, adhesions, and Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) - influences tumor-immune interactions and immunotherapeutic efficacy. Furthermore, biophysical methods such as fluidic systems and mechanoactivation schemes can improve the controllability and manufacturing of engineered T cells, with potential for increasing therapeutic efficacy and specificity. This review focuses on leveraging advances in immune biophysics and mechanobiology toward improving chimeric antigen receptor (CAR) T-cell and anti-programmed cell death protein 1 (anti-PD-1) therapies.

Microbiologic findings in feedlot cattle with acute interstitial pneumonia.

OBJECTIVE: To test the hypothesis that feedlot cattle with acute interstitial pneumonia (AIP) have bacterial infection of the lung or liver and concurrent bovine respiratory syncytial virus (BRSV) infection significantly more often than pen mates without AIP ANIMALS: 39 feedlot cattle with signs consistent with AIP and no history of treatment with antimicrobials and 32 healthy control cattle from the same pens. PROCEDURES: Lung and liver specimens were obtained postmortem for bacterial or mycoplasmal culture and histologic examination; lung tissue was assessed for BRSV infection immunohistochemically. RESULTS: Among affected cattle, 26 had AIP confirmed histologically. Lung tissue from 11 cattle with AIP yielded microbial respiratory tract pathogens on culture; tissues from control animals yielded no microbial growth. In 4 cattle with AIP and 2 control animals, liver abscesses were detected; bacteria were isolated from abscessed tissue in 3 and 1 of those animals, respectively. Immunohistochemically, 9 cattle with AIP and no control animals were BRSV-positive. Histologically, 9 AIP-affected cattle had only acute alveolar damage with exudation, and the other 17 had acute exudation with type II pneumocyte hyperplasia. No lesions of AIP were detected in control animals. Only 4 AIP-affected cattle had bacterial infection of the lung with concurrent BRSV infection. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that microbial respiratory tract pathogens are more common in cattle with AIP than in healthy pen mates. Control of bacterial pneumonia late in the feeding period may reduce the incidence of AIP at feedlots where AIP is a problem.