Programmable Bispecific Nano-immunoengager That Captures T Cells and Reprograms Tumor Microenvironment.

Immune checkpoint blockade (ICB) therapy has revolutionized clinical oncology. However, the efficacy of ICB therapy is limited by the ineffective infiltration of T effector (Teff) cells to tumors and the immunosuppressive tumor microenvironment (TME). Here, we report a programmable tumor cells/Teff cells bispecific nano-immunoengager (NIE) that can circumvent these limitations to improve ICB therapy. The peptidic nanoparticles (NIE-NPs) bind tumor cell surface α3ß1 integrin and undergo in situ transformation into nanofibrillar network nanofibers (NIE-NFs). The prolonged retained nanofibrillar network at the TME captures Teff cells via the activatable α4ß1 integrin ligand and allows sustained release of resiquimod for immunomodulation. This bispecific NIE eliminates syngeneic 4T1 breast cancer and Lewis lung cancer models in mice, when given together with anti-PD-1 antibody. The in vivo structural transformation-based supramolecular bispecific NIE represents an innovative class of programmable receptor-mediated targeted immunotherapeutics to greatly enhance ICB therapy against cancers.

Plasticity in floral longevity and sex-phase duration of Lobelia siphilitica in response to simulated pollinator declines.

PREMISE: Pollinator declines can reduce the quantity and quality of pollination services, resulting in less pollen deposited on flowers and lower seed production by plants. In response to these reductions, plant species that cannot autonomously self-pollinate and thus are dependent on pollinators to set seed could plastically adjust their floral traits. Such plasticity could increase the opportunity for outcross pollination directly, as well as indirectly by affecting inflorescence traits. METHODS: To test whether plants can respond to pollinator declines by plastically adjusting their floral traits, we simulated declines by experimentally reducing pollinator access to Lobelia siphilitica plants and measuring two traits of early- and late-season flowers: (1) floral longevity; and (2) sex-phase duration. To test whether plasticity in these floral traits affected inflorescence traits, we measured daily display size and phenotypic gender. RESULTS: We found that experimentally reducing pollination did not affect female-phase duration, but did extend the male-phase duration of early-season flowers by 13% and the longevity of late-season flowers by 12.8%. However, plants with an extended male phase did not have a more male-biased phenotypic gender, and plants with an extended floral longevity did not have a larger daily display. CONCLUSIONS: Our results suggest that plants can respond to pollinator declines by plastically adjusting both the longevity and sex-phase duration of their flowers. If this plasticity increases the opportunity for outcross pollination, then it could be one mechanism by which pollinator-dependent plant species maintain seed production as pollinators decline.

Independent representations of self-motion and object location in barrel cortex output.

During active tactile exploration, the dynamic patterns of touch are transduced to electrical signals and transformed by the brain into a mental representation of the object under investigation. This transformation from sensation to perception is thought to be a major function of the mammalian cortex. In primary somatosensory cortex (S1) of mice, layer 5 (L5) pyramidal neurons are major outputs to downstream areas that influence perception, decision-making, and motor control. We investigated self-motion and touch representations in L5 of S1 with juxtacellular loose-seal patch recordings of optogenetically identified excitatory neurons. We found that during rhythmic whisker movement, 54 of 115 active neurons (47%) represented self-motion. This population was significantly more modulated by whisker angle than by phase. Upon active touch, a distinct pattern of activity was evoked across L5, which represented the whisker angle at the time of touch. Object location was decodable with submillimeter precision from the touch-evoked spike counts of a randomly sampled handful of these neurons. These representations of whisker angle during self-motion and touch were independent, both in the selection of which neurons were active and in the angle-tuning preference of coactive neurons. Thus, the output of S1 transiently shifts from a representation of self-motion to an independent representation of explored object location during active touch.

Fluctuation Imaging of LRRK2 Reveals that the G2019S Mutation Alters Spatial and Membrane Dynamics.

Mutations within the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are the most common genetic cause of autosomal and sporadic Parkinson's disease (PD). LRRK2 is a large multidomain kinase that has reported interactions with several membrane proteins, including Rab and Endophilin, and has recently been proposed to function as a regulator of vesicular trafficking. It is unclear whether or how the spatiotemporal organization of the protein is altered due to LRRK2 activity. Therefore, we utilized fluctuation-based microscopy along with FLIM/FRET to examine the cellular properties and membrane recruitment of WT LRRK2-GFP (WT) and the PD mutant G2019S LRRK2-GFP (G2019S). We show that both variants can be separated into two distinct populations within the cytosol; a freely diffusing population associated with monomer/dimer species and a slower, likely vesicle-bound population. G2019S shows a significantly higher propensity to self-associate in both the cytosol and membrane regions when compared to WT. G2019S expression also resulted in increased hetero-interactions with Endophilin A1 (EndoA1), reduced cellular vesicles, and altered clathrin puncta dynamics associated with the plasma membrane. This finding was associated with a reduction in transferrin endocytosis in cells expressing G2019S, which indicates disruption of endocytic protein recruitment near the plasma membrane. Overall, this study uncovered multiple dynamic alterations to the LRRK2 protein as a result of the G2019S mutation-all of which could lead to neurodegeneration associated with PD.

Nanomedicine for Cystic Fibrosis.

Cystic fibrosis is a genetic disease affecting more than 70,000 people worldwide. Caused by a mutation in the CFTR gene, cystic fibrosis can result in difficulty breathing, widespread bacterial infections, edema, malnutrition, pancreatitis, and death. Current drug-based treatments struggle to reach the site of action due to the thick mucus, and only manage symptoms such as blocked airways, lung infections, and limited ability to digest food. Nanotechnology opens up possibilities for improved treatment strategies by focusing on drug penetration through the mucus lining, eliminating resulting bacterial infections, and targeting the underlying genetic cause of the disease. In this review, we present recent nanoparticle developments for cystic fibrosis, challenges in nanomedicine therapeutics, and future research directions in gene editing and nonviral vectors for gene delivery.