Table Of Contents Page, PNAS Volume 122, Number 45
Special Feature
Structural Immunotherapy: Breakthroughs in Vaccine Development Fueled by Nanotechnology
Structural immunotherapy relies on the structural features of immunotherapeutics in
addition to component identity to influence biodistribution, intra- or extracellular
localization, target engagement, and processing kinetics. This strategy is poised
to ...
Self-assembling protein nanoparticles are being increasingly utilized in the design
of next-generation vaccines due to their ability to induce antibody responses of superior
magnitude, breadth, and durability. Computational protein design offers a route ...
We describe the production and use of nanobody drug conjugates that comprise of VHHkappa, a nanobody that recognizes mouse immunoglobulin kappa light chains, and one or more
copies of the small molecule influenza virus neuraminidase (NA) inhibitor, ...
Vaccines induce specific immunity through antigen uptake and processing. However,
while nanoparticle vaccines have elevated uptake, the impact of intracellular protein
release and how this affects processing and downstream responses are not fully ...
In recent years, therapeutic cancer vaccines have been extensively investigated, aiming
to boost cancer-specific T cells crucial for antitumor activity. The effectiveness
of these vaccines is often limited by insufficient immune activation and suboptimal
...
Peptide therapeutic cancer vaccines are an attractive treatment modality for their
safety and manufacturability but have been hindered in clinical translation by low
immunogenicity and insufficient CD8+ T cell activation. We developed virus-inspired ...
Cancer cells comprise a significant proportion of the tumor microenvironment (TME)
and often have compromised expression or repression of cyclic GMP-AMP (cGAMP) synthase
(cGAS), which prevents effective stimulation of interferon genes (STING) signaling.
...
Toll-like receptor (TLR) agonists, as potent immunostimulatory adjuvants, play a critical
role in linking the innate and adaptive immune responses. However, their antitumor
effects as cancer immunotherapeutic agents have been limited. Here, we report our
...
Bispecific T cell engager (BiTE) therapeutics that link T cells and tumor cells to
induce tumor cell lysis have demonstrated great success in the clinic for the treatment
of many cancers. However, T cell exhaustion in the tumor microenvironment leads to
...
Lipid nanoparticles (LNPs) formulated with a neutral helper lipid can deliver RNA
to the liver in humans. However, clinically relevant delivery to other tissues has
remained challenging. To avoid the liver, scientists often add antibodies or helper
lipids ...
To mount a robust and durable immune response, the antigen in a vaccine must be processed
efficiently in the appropriate intracellular compartment. Here, we report an approach
for optimizing the antigen processing pathway and efficiency by using the ...
The cyclic GMP-AMP synthase-Stimulator of Interferon Genes (cGAS–STING) pathway is
an important DNA-sensing mechanism that increases T cell trafficking and activation
in tumors and reverses the immunosuppressive phenotype of myeloid cells. Therefore,
...
Despite the growing recognition of tertiary lymphoid structures (TLSs) as valuable
prognostic markers in certain cancer types, detailed studies on their development
and therapeutic function remain limited. This is partially due to the lack of appropriate
...
Staphylococcus aureus is the leading cause of global bacterial mortality. While S. aureus can cause a variety of diseases, orthopedic device infections are particularly challenging
due to the need for additional surgeries with associated morbidity. ...
Development of tolerogenic, antigen-specific immunotherapies could overcome limitations
of existing treatments for inflammatory autoimmune diseases by achieving potent, durable
remission without impacting healthy immune surveillance. Here, we deliver ...
This Week in PNAS
Opinion
Retrospective
Robert Haselkorn (1934–2025) began a long and impactful career during the early years
of nucleic acids research when the foundations of molecular biology were being laid.
Focusing first on plant viruses, and then also bacteriophage, he hit upon a ...
Commentaries
Letters
This article replies to:
Brief Reports
Local immigration raids expanded dramatically across the United States during the
first 2 mo of 2025. Anecdotal accounts suggest that these raids increased student
absences from schools because parents fear being separated from their children. This
study ...
Benign and malignant (cancerous) tumors differ markedly in their impact on organismal
fitness, yet studies in comparative oncology rarely distinguish between them. Using
a Bayesian phylogenetic framework across birds and mammals, we show that while both
...
Physical Sciences
Applied Physical Sciences
The development of microfluidic technologies has enabled chemical and biological analysis
systems with increased functionality, complexity, and parallelization. These functionalities
often drive the creation and control of complex and dynamic fluidic ...
Astronomy
The generation of dense electron–positron pair beams in the laboratory can enable
direct tests of theoretical models of γ-ray bursts and active galactic nuclei. We have successfully achieved this using ultrarelativistic
protons accelerated by the Super ...
Biophysics and Computational Biology
Mammalian cells sense and respond to environmental changes using a complex and intelligent
system that integrates chemical and mechanical signals. The transduction of mechanical
cues into chemical changes modulates cell physiology, allowing a cell to ...
The mechanisms by which two sister chromosomes separate and partition into daughter
cells in bacteria remain poorly understood. A recent theoretical model has proposed
that out-of-equilibrium central dogma reactions involving mRNA and ribosomes play
a ...
Modeling the conformational heterogeneity of protein–small molecule interactions is
important for understanding natural systems and evaluating designed systems but remains
an outstanding challenge. We reasoned that while residue-level descriptions of ...
Extracellular ATP (eATP) has emerged as a crucial signaling molecule across eukaryotic
and prokaryotic domains, modulating diverse cellular functions by activating purinergic
receptors to initiate intracellular signaling cascades. However, the structural ...
RNA molecules play central roles in the assembly and regulation of biomolecular condensates,
often in concert with proteins containing low complexity RNA-binding domains. Recently,
it has been shown that RNA can phase-separate in the absence of any ...
Alzheimer neurodegenerative disease (AD) has had a major impact worldwide, with no
effective drugs for treatment. We discovered and reported earlier that neurotrophic
factor-α1 (NF-α1)/carboxypeptidase E (CPE) reversed neurodegeneration and cognitive
...
Plants responding to excessive soil salinity by discharging brine onto their leaf
surface risk dehydration through the osmotic continuity between the living tissue
and the surface brine, which further enriches with evaporation. Cuticle cracks have
long ...
Chemistry
Lithium metal is widely recognized as the ultimate anode material for next-generation
lithium batteries due to its superior specific capacity. However, microscopic crystallographic
heterogeneity caused by crystal faces and grain boundaries leads to ...
Solid–electrolyte interphase (SEI) is the critical component in all advanced battery
chemistries, whose ionic transport and electron leakage behaviors remain least understood
among all battery components. Here, using unique in situ liquid secondary ion ...
Metalloenzymes couple substrate binding and formation of oxidative intermediates to
minimize unwanted side reactions. However, the molecular details of such coupling
frequently remain ambiguous. Radical S-adenosyl-L-methionine (SAM) enzymes constitute one ...
Polyketides represent a structurally diverse class of natural products with a wide
range of biological functions, including antimicrobial activity, defense responses,
developmental regulation, pigmentation, and intercellular and intracellular ...
Computer Sciences
The US Decennial Census serves as the foundation for many high-profile policy decision-making
processes, including federal funding allocation and redistricting. In 2020, the Census
Bureau adopted differential privacy to protect the confidentiality of ...
Earth, Atmospheric, and Planetary Sciences
Previous studies focusing on the electrical conductivity and thermal evolution of
an early magma ocean at the base of Earth’s mantle have found that basal magma ocean
(BMO) convection could have produced the ancient geomagnetic field. By advances in
high-...
The contribution of terrestrial dissolved organic matter (DOM) to the ocean has been
an enigma for decades. Tracking terrestrial DOM in the ocean has proven challenging
due to factors such as the instability of terrestrial biomarkers, indistinguishable
...
Mathematics
We propose a mathematical framework that we call quantum, higher-order Fourier analysis.
This generalizes the classical theory of higher-order Fourier analysis, which led
to many recent advances in number theory and combinatorics. We define a family of
“...
Physics
Deterministic optimization algorithms unequivocally partition a complex energy landscape
into inherent structures (ISs) and their respective basins of attraction. Can these
basins be defined solely through geometric principles? This question is paramount
...
Silica is the paradigmatic network glass-former and understanding its response to
pressure is essential for comprehending the mechanical properties of silica-based
materials and the behavior of silicate melts in the Earth’s interior. While pressure
(P)-...
Electronic flat bands associated with quenched kinetic energy and heavy electron mass
have attracted great interest for promoting strong electronic correlations and emergent
phenomena such as high-temperature charge fractionalization and ...
Statistics
Many existing approaches to generalizing statistical inference amid distribution shift
operate under the covariate shift assumption, which posits that the conditional distribution
of unobserved variables given observable ones is invariant across ...
Sustainability Science
Biomanufactured fibers produced through fermentation processes provide a promising
pathway to decouple textile production from agricultural land. This would free up
arable land for food cultivation and contribute to the United Nations Sustainable
...
Social Sciences
Economic Sciences
Recent research in psychology, management, and more recently in economics, highlights
the role of individual managers and their behavior in shaping employee performance.
While emerging literature on harmful managerial behavior has focused primarily on
...
Political Sciences
Expressions of dissent against authority are an important feature of most societies,
and efforts to suppress such expressions are common. Modern digital communications,
social media, and Internet surveillance and censorship technologies are changing the
...
Psychological and Cognitive Sciences
Self-control—the ability to pursue long-term goals over short-term temptations—is
a critical faculty of human cognition, but the cognitive processes enabling self-control
are not well understood. Traditional models have focused on impulse inhibition: ...
Drug-related memories can hinder abstinence goals in drug addiction. Promoting nondrugmemories
via ventromedial prefrontal cortex (vmPFC)- and amygdala-guided extinctionyields mixed
success. Postretrieval extinction (RE) destabilizes and updates ...
Social Sciences
Many existing approaches to generalizing statistical inference amid distribution shift
operate under the covariate shift assumption, which posits that the conditional distribution
of unobserved variables given observable ones is invariant across ...
The US Decennial Census serves as the foundation for many high-profile policy decision-making
processes, including federal funding allocation and redistricting. In 2020, the Census
Bureau adopted differential privacy to protect the confidentiality of ...
Biological Sciences
Anthropology
The Crimean Peninsula contains several important Middle and Upper Paleolithic sites,
including Starosele, Kabazi II, and Siuren I. The region has been considered a potential
refugium for Neanderthals before their replacement by Homo sapiens. However, no ...
Applied Biological Sciences
Biomanufactured fibers produced through fermentation processes provide a promising
pathway to decouple textile production from agricultural land. This would free up
arable land for food cultivation and contribute to the United Nations Sustainable
...
Cellulosic biomass represents a promising feedstock for biofuel and biochemical production.
However, its recalcitrant structure strongly hinders enzymatic degradation. Cellulosomes
are large multienzyme complexes, highly efficient at degrading cellulose. ...
Biochemistry
Metalloenzymes couple substrate binding and formation of oxidative intermediates to
minimize unwanted side reactions. However, the molecular details of such coupling
frequently remain ambiguous. Radical S-adenosyl-L-methionine (SAM) enzymes constitute one ...
The β-ketoacyl-acyl carrier protein (ACP) synthases are pivotal elongation enzymes
that catalyze the condensation of acyl-CoA or acyl-ACP with malonyl-ACP to produce
β-ketoacyl-ACP. Among these, the homologous enzymes FabH (β-ketoacyl-ACP synthase
III) ...
G protein–coupled receptors (GPCRs) are prominent drug targets that have attracted
intensive efforts in drug screening. Binding-based screening methods for GPCR ligands
often require conformationally stable, purified receptors. However, obtaining large
...
Retinol-binding protein 4 (RBP4) is the sole specific serum carrier of vitamin A,
delivering it from the hepatic stores to the peripheral organs in a complex with retinol
(ROH) and transthyretin (TTR). Regulators of hepatic mobilization aside from vitamin
...
Biophysics and Computational Biology
The mechanisms by which two sister chromosomes separate and partition into daughter
cells in bacteria remain poorly understood. A recent theoretical model has proposed
that out-of-equilibrium central dogma reactions involving mRNA and ribosomes play
a ...
RNA molecules play central roles in the assembly and regulation of biomolecular condensates,
often in concert with proteins containing low complexity RNA-binding domains. Recently,
it has been shown that RNA can phase-separate in the absence of any ...
Drug resistance poses a major global health challenge, necessitating the development
of effective therapeutic strategies. The main challenge is to predict drug-resistant
mutations and design drugs that retain efficacy against such evolving targets. Our
...
Cell Biology
Mammalian cells sense and respond to environmental changes using a complex and intelligent
system that integrates chemical and mechanical signals. The transduction of mechanical
cues into chemical changes modulates cell physiology, allowing a cell to ...
Receptor activator of nuclear factor kappa B ligand (RANKL) is an essential cytokine
that induces osteoclastic differentiation by monocyte-macrophage lineage precursors.
Here, we showed that in addition to its conventional action, RANKL controls vascular
...
The fetomaternal interface is replete with glycan-binding proteins (GBPs) that can
interact with cell surface glycoprotein counterreceptors to regulate placental function.
Here, we interrogate the role of galectin-3, a GBP that controls placental ...
The MEK–ERK pathway is a key driver of hepatocellular carcinoma (HCC) pathogenesis,
and BRAF mutations, particularly BRAFV600E, can contribute to its activation. Although BRAFV600E mutations are rare in human HCC, they do occur, yet their physiologic ...
Environmental Sciences
The contribution of terrestrial dissolved organic matter (DOM) to the ocean has been
an enigma for decades. Tracking terrestrial DOM in the ocean has proven challenging
due to factors such as the instability of terrestrial biomarkers, indistinguishable
...
Evolution
Speciation often results from the accumulation of reproductive isolation associated
with lineage divergence, but secondary contact between diverged lineages can reshape
the trajectory of speciation and reveal its underlying processes. The Indonesian ...
The systematic variation in relative brain size among vertebrate classes remains poorly
understood. Here, based on the expensive brain hypothesis, we propose that two broad
constraints explain much of the variation: 1) the ability to produce large ...
Genetics
RNA base editing has the capability to rewrite genetic codes while offering improved
safety due to its reversibility and temporal-spatial tunability. The development of
cytosine-to-uridine editors faces issues of DNA mutagenic activity of APOBECs and
the ...
Immunology and Inflammation
Microtubule-associated protein 1A/1B-light chain 3 (LC3)-associated phagocytosis (LAP)
plays a critical role in host defense against invading pathogens, including Listeria monocytogenes (Listeria. monocytogenes), Salmonella typhimurium (S. typhimurium), ...
Microbiology
Polyketides represent a structurally diverse class of natural products with a wide
range of biological functions, including antimicrobial activity, defense responses,
developmental regulation, pigmentation, and intercellular and intracellular ...
The peptidoglycan (PG) cell wall is critical for bacterial growth and survival and
is a primary antibiotic target. MreD is an essential accessory factor of the Rod complex,
which carries out PG synthesis during elongation, yet little is known about how ...
Metabolic pathways are typically dysregulated in cancer to support critical cellular
processes. In response to metabolic disturbances, cancer cells preferentially manipulate
stress sensors to enhance their adaptability. Sestrin 2 (SESN2), a highly ...
The HIV type 1 (HIV-1) accessory proteins Virion Infectivity Factor (Vif) and Viral
Protein R (Vpr) are essential for efficient virus replication in vivo. Vif mediates
degradation of host restriction factor APOBEC3G, while Vpr modulates the host cell
...
Natural genetic code expansion is a phenomenon wherein an additional amino acid is
encoded by a stop codon. These nonstandard amino acids are beneficial as they facilitate
novel biochemical reactions. However, code expansion leads to ambiguity at the ...
Zoonotic H7N9 avian influenza virus infection remains a global concern because of
its pandemic potential. Therefore, developing effective antibodies and vaccines against
H7N9 is vital for preventing and controlling major outbreaks. Here, we isolated a
...
Microbial communities inhabiting plants have emerged as crucial factors in regulating
plant health and defense against disease-causing pathogens. The yeast Moesziomyces bullatus ex. Albugo (MbA) on Arabidopsis produces a glycoside hydrolase 25 (GH25) ...
Neuroscience
Alzheimer neurodegenerative disease (AD) has had a major impact worldwide, with no
effective drugs for treatment. We discovered and reported earlier that neurotrophic
factor-α1 (NF-α1)/carboxypeptidase E (CPE) reversed neurodegeneration and cognitive
...
Drug-related memories can hinder abstinence goals in drug addiction. Promoting nondrugmemories
via ventromedial prefrontal cortex (vmPFC)- and amygdala-guided extinctionyields mixed
success. Postretrieval extinction (RE) destabilizes and updates ...
Memories are believed to be stored in synapses and retrieved by reactivating neural
ensembles. Learning alters synaptic weights, which can interfere with previously stored
memories that share the same synapses, creating a trade-off between plasticity and
...
Recent advances in large-scale recording technology have spurred inquiries into the
high-dimensional geometry of the neural code. However, characterizing this geometry
from noisy neural responses, particularly in datasets with more neurons than trials,
...
The population receptive field (pRF) approach to functional measurement of the sensory
properties of magnetic resonance (MR)-identified locations in the human brain was
extended to include the third dimension of binocular depth. In total, pRFs were ...
Mechanoelectrical transduction (MET) channels in cochlear hair cells are gated by
tip links through a mechanism that is poorly defined. LHFPL5 interacts with the tip-link
component PCDH15 and the MET-channel component TMC1, suggesting that LHFPL5 ...
Human neural networks of interconnected neurons have evolved to be remarkably efficient
and are capable of learning and memory through the brain’s synaptic plasticity, including
short-term plasticity (STP), and long-term potentiation (LTP) and depression (...
PIEZO channels are mechanical force sensors involved in various biological processes,
including somatosensation. To date, only a few PIEZO-binding partners have been identified,
including MyoD-family inhibitor proteins (MDFI and MDFIC). Here, we show that ...
Research indicates that midbrain dopaminergic neurons encode reward prediction error
(RPE) signals involved in positive reinforcement learning. However, studies on dopamine’s
role in negative reinforcement learning (NRL) are scarce. Learning to escape ...
Normalization is a fundamental and ubiquitous neuronal computation that stabilizes
activity across populations of neurons and preserves stimulus selectivity. While it
is observed throughout the visual system, normalization may be particularly important
in ...
Physiology
Although mechanical tension from luminal distension is a primary regulator of gut
motility, we reveal a parallel chemosensory pathway wherein long-chain unsaturated
free fatty acids (LUFFAs) from dietary or enterobacterial sources directly modulate
...
Plant Biology
Plants responding to excessive soil salinity by discharging brine onto their leaf
surface risk dehydration through the osmotic continuity between the living tissue
and the surface brine, which further enriches with evaporation. Cuticle cracks have
long ...
Since its initial identification as the receptor for Rapid Alkalinization Factor 1
(RALF1), FERONIA (FER) receptor kinase has emerged as a central signaling hub coordinating
plant development, stress adaptation, and immune responses. Nevertheless, ...
Calcium (Ca2+) signaling plays a crucial role in plant immunity, regulating both pattern-triggered
immunity (PTI) through cell-surface receptors and effector-triggered immunity (ETI)
via intracellular nucleotide-binding, leucine-rich repeat receptors (...
Abscisic acid (ABA) is pivotal in seed development, yet its role in iron (Fe) homeostasis
remains unclear. Here, we reveal a PYLs–bHLH IVc–YSLs module that mediates ABA-dependent
suppression of seed Fe accumulation in Arabidopsis. During seed maturation, ...
Sustainability Science
Agricultural landscapes provide material, nonmaterial, and regulating contributions
that affect human well-being (nature’s contributions to people, NCP). The responses
of these NCP to land-use patterns depend on supporting biota with different habitat
...
Corrections
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%20_%20PNAS_files/pnas_002.webp "View the PNAS Table of Contents Vol.122; No.45")
Cover image: Pictured is an illustration visualizing vaccines as carefully engineered, modular, and tunable nanostructures. A collection of articles in the Structural Immunotherapy: Breakthroughs in Vaccine Development Fueled by Nanotechnology Special Feature explores how nanoscience is revolutionizing vaccine design through structural immunotherapy, which emphasizes the spatial arrangement of vaccine components to optimize immune response. Together, the articles highlight the development of nanomaterials, including spherical nucleic acids, lipid nanoparticles, and polymers, to treat cancer, infectious diseases, and autoimmune disorders. See the Introduction to the Special Feature, e2409553122. Image credit: Akanksha Mahajan (Washington University in St. Louis, St. Louis, MO).
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