Organelle-specific targeting of polymersomes into the cell nucleus

Zelmer, Christina; Zweifel, Ludovit; Kapinos, Larisa E.; Craciun, Ioana; Güven, Zekiye Pelin; Palivan, Cornelia G.; Lim, Roderick Y. H.

doi:10.1073/pnas.1916395117

Cited by 67 publications

(41 citation statements)

References 56 publications

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“…For the larger MS2, more than 30 NLSs were required to detect a clear signal. It is important to note that in addition to cargo shape ( Mohr et al, 2009 ), its mechanical stability and rigidity are likely to play a role in nucleocytoplasmic transport: the import rate of proteins is inversely correlated with its mechanical stability ( Infante et al, 2019 ), and flexibility is likely relevant for the transport of large deformable synthetic cargoes, such as polymer vesicles ( Zelmer et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Molecular determinants of large cargo transport into the nucleus

Paci

Zheng

Caria

et al. 2020

eLife

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Nucleocytoplasmic transport is tightly regulated by the nuclear pore complex (NPC). Among the thousands of molecules that cross the NPC, even very large (>15 nm) cargoes such as pathogens, mRNAs and pre-ribosomes can pass the NPC intact. For these cargoes, there is little quantitative understanding of the requirements for their nuclear import, especially the role of multivalent binding to transport receptors via nuclear localisation sequences (NLSs) and the effect of size on import efficiency. Here, we assayed nuclear import kinetics of 30 large cargo models based on four capsid-like particles in the size range of 17–36 nm, with tuneable numbers of up to 240 NLSs. We show that the requirements for nuclear transport can be recapitulated by a simple two-parameter biophysical model that correlates the import flux with the energetics of large cargo transport through the NPC. Together, our results reveal key molecular determinants of large cargo import in cells.

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Section: Discussionmentioning

confidence: 99%

Molecular determinants of large cargo transport into the nucleus

Paci

Zheng

Caria

et al. 2020

eLife

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“…Polymersomes are artificial vesicles, with membranes made using amphiphilic block copolymers. They are comparable to liposomes, and are often locally responsive, but are reported to have improved stability and cargo-retention efficiency 39 , making them effective vehicles for the delivery of therapeutics to the cytosol 40,41 . Some polymers which are commonly copolymerized for these applications include poly(ethylene glycol) Overview highlighting some of the biological barriers that nanoparticles (NPs) can overcome (inner ring) and precision medicine applications that may benefit from NPs (outer ring).…”

Section: Polymeric Npsmentioning

confidence: 99%

Engineering precision nanoparticles for drug delivery

Mitchell

Billingsley

Haley

et al. 2020

Nat Rev Drug Discov

4,092

2,814

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In recent years, the development of nanoparticles has expanded into a broad range of clinical applications. Nanoparticles have been developed to overcome the limitations of free therapeutics and navigate biological barriers — systemic, microenvironmental and cellular — that are heterogeneous across patient populations and diseases. Overcoming this patient heterogeneity has also been accomplished through precision therapeutics, in which personalized interventions have enhanced therapeutic efficacy. However, nanoparticle development continues to focus on optimizing delivery platforms with a one-size-fits-all solution. As lipid-based, polymeric and inorganic nanoparticles are engineered in increasingly specified ways, they can begin to be optimized for drug delivery in a more personalized manner, entering the era of precision medicine. In this Review, we discuss advanced nanoparticle designs utilized in both non-personalized and precision applications that could be applied to improve precision therapies. We focus on advances in nanoparticle design that overcome heterogeneous barriers to delivery, arguing that intelligent nanoparticle design can improve efficacy in general delivery applications while enabling tailored designs for precision applications, thereby ultimately improving patient outcome overall.

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“…Time-correlated single photon counting setup. A detailed description of the timeresolved fluorescence microscopy setup can be found elsewhere [30]. In short, FLIM images and lifetime-filtered point FLCS measurements were performed on an Olympus IX73 inverted PLOS BIOLOGY microscope stand equipped with a 1.4 NA oil-immersion 100× superapochromat objective (UplanSApo; Olympus) and suitable emission and excitation bandpass filters (Semrock and AHF).…”

Section: Plos Biologymentioning

confidence: 99%

Subpopulations of sensorless bacteria drive fitness in fluctuating environments

et al. 2020

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Populations of bacteria often undergo a lag in growth when switching conditions. Because growth lags can be large compared to typical doubling times, variations in growth lag are an important but often overlooked component of bacterial fitness in fluctuating environments. We here explore how growth lag variation is determined for the archetypical switch from glucose to lactose as a carbon source in Escherichia coli. First, we show that single-cell lags are bimodally distributed and controlled by a single-molecule trigger. That is, gene expression noise causes the population before the switch to divide into subpopulations with zero and nonzero lac operon expression. While “sensorless” cells with zero preexisting lac expression at the switch have long lags because they are unable to sense the lactose signal, any nonzero lac operon expression suffices to ensure a short lag. Second, we show that the growth lag at the population level depends crucially on the fraction of sensorless cells and that this fraction in turn depends sensitively on the growth condition before the switch. Consequently, even small changes in basal expression can significantly affect the fraction of sensorless cells, thereby population lags and fitness under switching conditions, and may thus be subject to significant natural selection. Indeed, we show that condition-dependent population lags vary across wild E. coli isolates. Since many sensory genes are naturally low expressed in conditions where their inducer is not present, bimodal responses due to subpopulations of sensorless cells may be a general mechanism inducing phenotypic heterogeneity and controlling population lags in switching environments. This mechanism also illustrates how gene expression noise can turn even a simple sensory gene circuit into a bet hedging module and underlines the profound role of gene expression noise in regulatory responses.

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Organelle-specific targeting of polymersomes into the cell nucleus

Cited by 67 publications

References 56 publications

Molecular determinants of large cargo transport into the nucleus

Molecular determinants of large cargo transport into the nucleus

Engineering precision nanoparticles for drug delivery

Subpopulations of sensorless bacteria drive fitness in fluctuating environments

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