Table Of Contents Page, PNAS Volume 121, Number 11
Special Feature
Nanoparticles for RNA Therapeutics
Cell-type-specific in vivo delivery of genome editing molecules is the next breakthrough
that will drive biological discovery and transform the field of cell and gene therapy.
Here, we discuss recent advances in the delivery of CRISPR-Cas genome editors ...
Nanoparticle-based RNA delivery has shown great progress in recent years with the
approval of two mRNA vaccines for Severe Acute Respiratory Syndrome Coronavirus 2
(SARS-CoV-2) and a liver-targeted siRNA therapy. Here, we discuss the preclinical
and ...
Carriers for RNA delivery must be dynamic, first stabilizing and protecting therapeutic
RNA during delivery to the target tissue and across cellular membrane barriers and
then releasing the cargo in bioactive form. The chemical space of carriers ranges
...
Lipid nanoparticles (LNPs) have recently emerged as a powerful and versatile clinically
approved platform for nucleic acid delivery, specifically for mRNA vaccines. A major
bottleneck in the field is the release of mRNA-LNPs from the endosomal pathways ...
RNA interference (RNAi) therapeutics are an emerging class of medicines that selectively
target mRNA transcripts to silence protein production and combat disease. Despite
the recent progress, a generalizable approach for monitoring the efficacy of RNAi
...
A number of endogenous genes in the human genome encode retroviral gag-like proteins, which were domesticated from ancient retroelements. The paraneoplastic
Ma antigen (PNMA) family members encode a gag-like capsid domain, but their ability to assemble as ...
Rapid advances in nucleic acid therapies highlight the immense therapeutic potential
of genetic therapeutics. Lipid nanoparticles (LNPs) are highly potent nonviral transfection
agents that can encapsulate and deliver various nucleic acid therapeutics, ...
Lipid nanoparticle (LNP) formulations are a proven method for the delivery of nucleic
acids for gene therapy as exemplified by the worldwide rollout of LNP-based RNAi therapeutics
and mRNA vaccines. However, targeting specific tissues or cells is still a ...
Treating pregnancy-related disorders is exceptionally challenging because the threat
of maternal and/or fetal toxicity discourages the use of existing medications and
hinders new drug development. One potential solution is the use of lipid nanoparticle
(...
Adding a cationic helper lipid to a lipid nanoparticle (LNP) can increase lung delivery
and decrease liver delivery. However, it remains unclear whether charge-dependent
tropism is universal or, alternatively, whether it depends on the component that is
...
Lipid nanoparticles (LNPs) largely rely on ionizable lipids to yield successful nucleic
acid delivery via electrostatic disruption of the endosomal membrane. Here, we report
the identification and evaluation of ionizable lipids containing a thiophene ...
This Week in PNAS
At the National Academies
In recent years, many questions have been raised about whether public confidence in
science is changing. To clarify recent trends in the public’s confidence and factors
that are associated with these feelings, an effort initiated by the National Academies’...
Retrospective
Profile
Commentaries
Perspective
Phytoplankton and sea ice algae are traditionally considered to be the main primary
producers in the Arctic Ocean. In this Perspective, we explore the importance of benthic
primary producers (BPPs) encompassing microalgae, macroalgae, and seagrasses, ...
Letters
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Brief Reports
In amniote limbs, Fibroblast Growth Factor 10 (FGF10) is essential for limb development,
but whether this function is broadly conserved in tetrapods and/or involved in adult
limb regeneration remains unknown. To tackle this question, we established Fgf10 ...
According to Dollo’s Law of irreversibility in evolution, a lost structure is usually
considered to be unable to reappear in evolution due to the accumulation over time
of mutations in the genes required for its formation. Cypriniform fish are a classic
...
Polynyas, areas of open water embedded within sea ice, are a key component of ocean–atmosphere
interactions that act as hotspots of sea-ice production, bottom-water formation, and
primary productivity. The specific drivers of polynya dynamics remain, ...
Physical Sciences
Applied Mathematics
We propose a method for imaging in scattering media when large and diverse datasets
are available. It has two steps. Using a dictionary learning algorithm the first step
estimates the true Green’s function vectors as columns in an unordered sensing ...
Applied Physical Sciences
We introduce MINFLUX localization with interferometric illumination through opposing
objective lenses for maximizing the attainable precision in 3D-localization of single
inelastic scatterers, such as fluorophores. Our 4Pi optical configuration employs
...
An unstable density stratification between two fluids mixes spontaneously under the
effect of gravity, a phenomenon known as Rayleigh–Taylor (RT) turbulence. If the two
fluids are immiscible, for example, oil and water, surface tension prevents ...
In this work, we report a direct measurement of the forces exerted by a tubulin/kinesin
active nematic gel as well as its complete rheological characterization, including
the quantification of its shear viscosity, η, and its activity parameter, α. For ...
Nitrogen-vacancy (NV) centers in diamond are a promising platform for nanoscale NMR
sensing. Despite significant progress toward using NV centers to detect and localize
nuclear spins down to the single spin level, NV-based spectroscopy of individual,
...
The usual basis to analyze heat transfer within materials is the equation formulated
200 years ago, Fourier’s law, which is identical mathematically to the mass diffusion
equation, Fick’s law. Revisiting this assumption regarding heat transport within ...
Aluminum nanocrystals (AlNCs) are of increasing interest as sustainable, earth-abundant
nanoparticles for visible wavelength plasmonics and as versatile nanoantennas for
energy-efficient plasmonic photocatalysis. Here, we show that annealing AlNCs under
...
Biophysics and Computational Biology
By masterfully balancing directed growth and passive mechanics, plant roots are remarkably
capable of navigating complex heterogeneous environments to find resources. Here,
we present a theoretical and numerical framework which allows us to interrogate ...
Recent developments in synthetic biology, next-generation sequencing, and machine
learning provide an unprecedented opportunity to rationally design new disease treatments
based on measured responses to gene perturbations and drugs to reprogram cells. The
...
Identifying the two substrate water sites of nature’s water-splitting cofactor (Mn4CaO5 cluster) provides important information toward resolving the mechanism of O-O bond
formation in Photosystem II (PSII). To this end, we have performed parallel ...
Elastin is an extracellular matrix material found in all vertebrates. Its reversible
elasticity, robustness, and low stiffness are essential for the function of arteries,
lungs, and skin. It is among the most resilient elastic materials known: During a
...
Proton-powered c-ring rotation in mitochondrial ATP synthase is crucial to convert
the transmembrane protonmotive force into torque to drive the synthesis of adenosine
triphosphate (ATP). Capitalizing on recent cryo-EM structures, we aim at a structural
...
T cells help orchestrate immune responses to pathogens, and their aberrant regulation
can trigger autoimmunity. Recent studies highlight that a threshold number of T cells
(a quorum) must be activated in a tissue to mount a functional immune response. ...
Chemistry
Self-assembled DNA crystals offer a precise chemical platform at the ångström-scale
for DNA nanotechnology, holding enormous potential in material separation, catalysis,
and DNA data storage. However, accurately controlling the crystallization kinetics
of ...
Silicone-based elastomers (SEs) have been extensively applied in numerous cutting-edge
areas, including flexible electronics, biomedicine, 5G smart devices, mechanics, optics,
soft robotics, etc. However, traditional strategies for the synthesis of ...
Developing cost-effective and high-performance electrocatalysts for oxygen reduction
reaction (ORR) is critical for clean energy generation. Here, we propose an approach
to the synthesis of iron phthalocyanine nanotubes (FePc NTs) as a highly active and
...
Autoimmune and inflammatory diseases are highly complex, limiting treatment and the
development of new therapies. Recent work has shown that cell-free DNA bound to biological
microparticles is linked to systemic lupus erythematosus, a prototypic ...
Water is known to play an important role in collagen self-assembly, but it is still
largely unclear how water–collagen interactions influence the assembly process and
determine the fibril network properties. Here, we use the HO/DO isotope effect on the ...
Earth, Atmospheric, and Planetary Sciences
Today, relatively warm Circumpolar Deep Water is melting Thwaites Glacier at the base
of its ice shelf and at the grounding zone, contributing to significant ice retreat.
Accelerating ice loss has been observed since the 1970s; however, it is unclear when
...
The projected changes in the hydrological cycle under global warming remain highly
uncertain across current climate models. Here, we demonstrate that the observational
past warming trend can be utilized to effectively co1nstrain future projections in
mean ...
Observational data have long suggested that in the tropics, when the troposphere locally
warms, the lower stratosphere locally cools. Here, the observed anti-correlation between
tropospheric and lower stratospheric temperature is confirmed—the lower ...
Engineering
Enzymatic reactions in solution drive the convection of confined fluids throughout
the enclosing chambers and thereby couple the processes of reaction and convection.
In these systems, the energy released from the chemical reactions generates a force,
...
Evaluating the ability of cytotoxic T lymphocytes (CTLs) to eliminate tumor cells
is crucial, for instance, to predict the efficiency of cell therapy in personalized
medicine. However, the destruction of a tumor by CTLs involves CTL migration in the
extra-...
Water–energy sustainability will depend upon the rapid development of advanced pressure-driven
separation membranes. Although energy-efficient, water-treatment membranes are constrained
by ubiquitous fouling, which may be alleviated by engineering self-...
Chiral plasmonic surfaces with 3D “forests” from nanohelicoids should provide strong
optical rotation due to alignment of helical axis with propagation vector of photons.
However, such three-dimensional nanostructures also demand multi-step ...
Environmental Sciences
Heterogeneous high-valent cobalt-oxo [≡Co(IV)=O] is a widely focused reactive species
in oxidant activation; however, the relationship between the catalyst interfacial
defects and ≡Co(IV)=O formation remains poorly understood. Herein, photoexcited oxygen
...
The electro-Fenton process is a state-of-the-art water treatment technology used to
remove organic contaminants. However, the low O2 utilization efficiency (OUE, <1%) and high energy consumption remain the biggest
obstacles to practical application. Here, ...
Soil organic carbon (SOC) mineralization is a key component of the global carbon cycle.
Its temperature sensitivity Q10 (which is defined as the factor of change in mineralization with a 10 °C temperature
increase) is crucial for understanding the carbon ...
Physics
The interplay of charge, spin, lattice, and orbital degrees of freedom in correlated
materials often leads to rich and exotic properties. Recent studies have brought new
perspectives to bosonic collective excitations in correlated materials. For example,
...
Social Sciences
Anthropology
Organized flaking techniques to obtain predetermined stone tools have been traced
back to the early Acheulean (also known as mode 2) in Africa and are seen as indicative
of the emergence of advanced technical abilities and in-depth planning skills among
...
Economic Sciences
To construct a stochastic version of [R. J. Barro, J. Polit. Econ. 87, 940–971 (1979)] normative model of tax rates and debt/GDP dynamics, we add risks
and markets for trading them along lines suggested by [K. J. Arrow, Rev. Econ. Stud. 31, 91–96 (1964)] ...
Psychological and Cognitive Sciences
An abundance of laboratory-based experiments has described a vigilance decrement of
reducing accuracy to detect targets with time on task, but there are few real-world
studies, none of which have previously controlled the environment to control for bias.
...
The neural correlates of sentence production are typically studied using task paradigms
that differ considerably from the experience of speaking outside of an experimental
setting. In this fMRI study, we aimed to gain a better understanding of syntactic
...
Sustainability Science
Climate change is expected to undermine population health and well-being in low- and
middle-income countries, but relatively few analyses have directly examined these
effects using individual-level data at global scales, particularly for reproductive-age
...
Biological Sciences
Anthropology
Organized flaking techniques to obtain predetermined stone tools have been traced
back to the early Acheulean (also known as mode 2) in Africa and are seen as indicative
of the emergence of advanced technical abilities and in-depth planning skills among
...
The early-life environment can profoundly shape the trajectory of an animal’s life,
even years or decades later. One mechanism proposed to contribute to these early-life
effects is DNA methylation. However, the frequency and functional importance of DNA
...
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Applied Biological Sciences
Evaluating the ability of cytotoxic T lymphocytes (CTLs) to eliminate tumor cells
is crucial, for instance, to predict the efficiency of cell therapy in personalized
medicine. However, the destruction of a tumor by CTLs involves CTL migration in the
extra-...
Thrombosis, induced by abnormal coagulation or fibrinolytic systems, is the most common
pathology associated with many life-threatening cardio-cerebrovascular diseases. However,
first-line anticoagulant drugs suffer from rapid drug elimination and risk of ...
Ribosomes are often used in synthetic biology as a tool to produce desired proteins
with enhanced properties or entirely new functions. However, repurposing ribosomes
for producing designer proteins is challenging due to the limited number of engineering
...
Biochemistry
Nuclear factor κB (NF-κB) is activated by various inflammatory and infectious molecules
and is involved in immune responses. It has been elucidated that ADP-β-D-manno-heptose
(ADP-Hep), a metabolite in gram-negative bacteria, activates NF-κB through alpha-...
Sponges (Porifera) contain many peptide-specialized metabolites with potent biological
activities and significant roles in shaping marine ecology. It is well established
that symbiotic bacteria produce bioactive “sponge” peptides, both on the ribosome
(...
Aromatic polyketides are renowned for their wide-ranging pharmaceutical activities.
Their structural diversity is mainly produced via modification of limited types of
basic frameworks. In this study, we characterized the biosynthesis of a unique basic
...
An RNA polymerase ribozyme that was obtained by directed evolution can propagate a
functional RNA through repeated rounds of replication and selection, thereby enabling
Darwinian evolution. Earlier versions of the polymerase did not have sufficient ...
Biophysics and Computational Biology
We introduce MINFLUX localization with interferometric illumination through opposing
objective lenses for maximizing the attainable precision in 3D-localization of single
inelastic scatterers, such as fluorophores. Our 4Pi optical configuration employs
...
Elastin is an extracellular matrix material found in all vertebrates. Its reversible
elasticity, robustness, and low stiffness are essential for the function of arteries,
lungs, and skin. It is among the most resilient elastic materials known: During a
...
Proton-powered c-ring rotation in mitochondrial ATP synthase is crucial to convert
the transmembrane protonmotive force into torque to drive the synthesis of adenosine
triphosphate (ATP). Capitalizing on recent cryo-EM structures, we aim at a structural
...
The potential of engineered enzymes in industrial applications is often limited by
their expression levels, thermal stability, and catalytic diversity. De novo enzyme
design faces challenges due to the complexity of enzymatic catalysis. An alternative
...
Mechanistic insights into the interactions of TAX1BP1 with RB1CC1 and mammalian ATG8 family proteins
TAX1BP1, a multifunctional autophagy adaptor, plays critical roles in different autophagy
processes. As an autophagy receptor, TAX1BP1 can interact with RB1CC1, NAP1, and mammalian
ATG8 family proteins to drive selective autophagy for relevant substrates. ...
The success of bacterial pathogens depends on the coordinated expression of virulence
determinants. Regulatory circuits that drive pathogenesis are complex, multilayered,
and incompletely understood. Here, we reveal that alterations in tRNA modifications
...
Proteins are a diverse class of biomolecules responsible for wide-ranging cellular
functions, from catalyzing reactions to recognizing pathogens. The ability to evolve
proteins rapidly and inexpensively toward improved properties is a common objective
for ...
Coordinated carbon and nitrogen metabolism is crucial for bacteria living in the fluctuating
environments. Intracellular carbon and nitrogen homeostasis is maintained by a sophisticated
network, in which the widespread signaling protein PII acts as a ...
Cell Biology
The transporter associated with antigen processing (TAP) is a key player in the major
histocompatibility class I-restricted antigen presentation and an attractive target
for immune evasion by viruses. Bovine herpesvirus 1 impairs TAP-dependent antigenic
...
Cytokinesis is the last step of cell division and is regulated by the small GTPase
RhoA. RhoA activity is required for all steps of cytokinesis, including prior to abscission
when daughter cells are ultimately physically separated. Like germ cells in all ...
Muscle regeneration is a complex process relying on precise teamwork between multiple
cell types, including muscle stem cells (MuSCs) and fibroadipogenic progenitors (FAPs).
FAPs are also the main source of intramuscular adipose tissue (IMAT). Muscles ...
Developmental Biology
The animal foregut is the first tissue to encounter ingested food, bacteria, and viruses.
We characterized the adult Drosophila foregut using transcriptomics to better understand
how it triages consumed items for digestion or immune response and manages ...
Ecology
Soil organic carbon (SOC) mineralization is a key component of the global carbon cycle.
Its temperature sensitivity Q10 (which is defined as the factor of change in mineralization with a 10 °C temperature
increase) is crucial for understanding the carbon ...
The composition of ecological communities varies not only between different locations
but also in time. Understanding the fundamental processes that drive species toward
rarity or abundance is crucial to assessing ecosystem resilience and adaptation to
...
Environmental Sciences
An unstable density stratification between two fluids mixes spontaneously under the
effect of gravity, a phenomenon known as Rayleigh–Taylor (RT) turbulence. If the two
fluids are immiscible, for example, oil and water, surface tension prevents ...
Evolution
Empiricists often struggle to apply game theory models to real-life cases of animal
cooperation. One reason is that many examples of cooperation occur in stable groups,
where individuals form social bonds that influence exchanges of help in ways that
are ...
Entire chromosomes are typically only transmitted vertically from one generation to
the next. The horizontal transfer of such chromosomes has long been considered improbable,
yet gained recent support in several pathogenic fungi where it may affect the ...
Insects lack acquired immunity and were thought to have no immune memory, but recent
studies reported a phenomenon called immune priming, wherein sublethal dose of pathogens
or nonpathogenic microbes stimulates immunity and prevents subsequential pathogen
...
Brown-and-white giant pandas (hereafter brown pandas) are distinct coat color mutants
found exclusively in the Qinling Mountains, Shaanxi, China. However, its genetic mechanism
has remained unclear since their discovery in 1985. Here, we identified the ...
Fluorescent proteins (FPs) are ubiquitous tools in research, yet their endogenous
functions in nature are poorly understood. In this work, we describe a combination
of functions for FPs in a clade of intertidal sea anemones whose FPs control a genetic
...
Warning coloration and Batesian mimicry are classic examples of Darwinian evolution,
but empirical evolutionary patterns are often paradoxical. We test whether foraging
costs predict the evolution of striking coloration by integrating genetic and ...
Flight was a key innovation in the adaptive radiation of insects. However, it is a
complex trait influenced by a large number of interacting biotic and abiotic factors,
making it difficult to unravel the evolutionary drivers. We investigate flight ...
Cellular metabolism evolves through changes in the structure and quantitative states
of metabolic networks. Here, we explore the evolutionary dynamics of metabolic states
by focusing on the collection of metabolite levels, the metabolome, which captures
...
View related content:
Genetics
The 1986 disaster at the Chornobyl Nuclear Power Plant transformed the surrounding
region into the most radioactive landscape known on the planet. Whether or not this
sudden environmental shift selected for species, or even individuals within a species,
...
Immunology and Inflammation
T cells help orchestrate immune responses to pathogens, and their aberrant regulation
can trigger autoimmunity. Recent studies highlight that a threshold number of T cells
(a quorum) must be activated in a tissue to mount a functional immune response. ...
Identification of mechanisms that program early effector T cells to either terminal
effector T (Teff) or memory T (Tm) cells has important implications for protective immunity against infections and
cancers. Here, we show that the cytosolic transcription ...
Natural killer (NK) cells are a vital part of the innate immune system capable of
rapidly clearing mutated or infected cells from the body and promoting an immune response.
Here, we find that NK cells activated by viral infection or tumor challenge ...
Viral mimicry of host cell structures has been postulated to curtail the B cell receptor
(BCR) repertoire against persisting viruses through tolerance mechanisms. This concept
awaits, however, experimental testing in a setting of natural virus–host ...
PD1 blockade therapy, harnessing the cytotoxic potential of CD8+ T cells, has yielded clinical success in treating malignancies. However, its efficacy
is often limited due to the progressive differentiation of intratumoral CD8+ T cells into a ...
The somatosensory nervous system surveils external stimuli at barrier tissues, regulating
innate immune cells under infection and inflammation. The roles of sensory neurons
in controlling the adaptive immune system, and more specifically immunity to the ...
Medical Sciences
An abundance of laboratory-based experiments has described a vigilance decrement of
reducing accuracy to detect targets with time on task, but there are few real-world
studies, none of which have previously controlled the environment to control for bias.
...
Microbiology
Endogenous viral elements (EVEs) are common genetic passengers in various protists.
Some EVEs represent viral fossils, whereas others are still active. The marine heterotrophic
flagellate Cafeteria burkhardae contains several EVE types related to the ...
Integrative and conjugative elements (ICEs) are self-transmissible mobile elements
that transfer functional genetic units across broad phylogenetic distances. Accessory
genes shuttled by ICEs can make significant contributions to bacterial fitness. Most
...
Neuroscience
The endothelial lining of cerebral microvessels is damaged relatively early after
cerebral ischemia/reperfusion (I/R) injury and mediates blood–brain barrier (BBB)
disruption, neurovascular injury, and long-term neurological deficits. I/R induces
BBB ...
Circadian clocks impose daily periodicities to behavior, physiology, and metabolism.
This control is mediated by a central clock and by peripheral clocks, which are synchronized
to provide the organism with a unified time through mechanisms that are not ...
Adaptive myelination is the emerging concept of tuning axonal conduction velocity
to the activity within specific neural circuits over time. Sound processing circuits
exhibit structural and functional specifications to process signals with microsecond
...
Retinitis pigmentosa (RP) is a common form of retinal dystrophy that can be caused
by mutations in any one of dozens of rod photoreceptor genes. The genetic heterogeneity
of RP represents a significant challenge for the development of effective therapies.
...
The specific roles that different types of neurons play in recovery from injury is
poorly understood. Here, we show that increasing the excitability of ipsilaterally
projecting, excitatory V2a neurons using designer receptors exclusively activated
by ...
Generation of defined neuronal subtypes from human pluripotent stem cells remains
a challenge. The proneural factor NGN2 has been shown to overcome experimental variability
observed by morphogen-guided differentiation and directly converts pluripotent ...
In order to deal with a complex environment, animals form a diverse range of neural
representations that vary across cortical areas, ranging from largely unimodal sensory
input to higher-order representations of goals, outcomes, and motivation. The ...
We present a comprehensive study on the non-invasive measurement of hippocampal perfusion.
Using high-resolution 7 tesla arterial spin labeling (ASL) data, we generated robust
perfusion maps and observed significant variations in perfusion among ...
Anxiety is a remarkably common condition among patients with pharyngitis, but the
relationship between these disorders has received little research attention, and the
underlying neural mechanisms remain unknown. Here, we show that the densely innervated
...
Visceral signals are constantly processed by our central nervous system, enable homeostatic
regulation, and influence perception, emotion, and cognition. While visceral processes
at the cortical level have been extensively studied using non-invasive ...
Plant Biology
By masterfully balancing directed growth and passive mechanics, plant roots are remarkably
capable of navigating complex heterogeneous environments to find resources. Here,
we present a theoretical and numerical framework which allows us to interrogate ...
Light-harvesting complexes (LHCs) are diversified among photosynthetic organisms,
and the structure of the photosystem I-LHC (PSI-LHCI) supercomplex has been shown
to be variable depending on the species of organisms. However, the structural and
...
Rubisco is the primary entry point for carbon into the biosphere. However, rubisco
is widely regarded as inefficient leading many to question whether the enzyme can
adapt to become a better catalyst. Through a phylogenetic investigation of the molecular
...
Systems Biology
Recent developments in synthetic biology, next-generation sequencing, and machine
learning provide an unprecedented opportunity to rationally design new disease treatments
based on measured responses to gene perturbations and drugs to reprogram cells. The
...
Correction
Retraction
Cover image: Pictured is a representation of a nanoparticle library. A collection of articles in the Nanoparticles for RNA Therapeutics Special Feature reviews advances in the discovery and characterization of nanoparticle-based delivery systems for RNA therapeutics. Together, the articles highlight the development of delivery systems targeting additional cell types, self-reporting RNA nanosystems, and biological studies on improving efficacy in delivery systems. See the Introduction to the Special Feature, e2315789121. Image credit: Christina Matacotta (photographer).
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