Biology subjects

Wang, K.

Publications and source records attributed to Wang, K..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Neural mechanisms of impaired self-compassion in depressed adolescents during social exclusion

Background: Self-compassion has shown to be an effective emotion regulation strategy, but its neural mechanisms remain understudied in adolescents with depression who suffer from social exclusion. This study employed event-related potentials to investigate the psychophysiological mechanisms underlying impaired self-compassion in adolescents with depression during social exclusion. Methods: Thirty-seven adolescents with major depressive disorder (age = 16.46 +/- 2.02) and thirty-two demographically matched healthy controls (age = 16.54 +/- 2.29) completed a social exclusion scenario imagination task. This task presented participants with social exclusion scenarios, asking them to imagine themselves as the excluded individual and subsequently rate their negative emotions. The regulation session required participants to use self-compassionate statements to regulate their emotional responses while imagining and rate how much self-compassion they have engaged in; the non-regulation required them not to use those statements and rate their negative emotions immediately following imagination. EEG signals were recorded during the task, and the late positive potential (LPP) was analyzed to examine the neural responses associated with self-compassion regulation following social exclusion. Results: Compared with the non-regulation condition, both groups showed less negative emotion during the self-compassion regulation condition. Adolescents with depression exhibited significantly lower self-compassion ratings than healthy controls, and showed a significantly smaller decrease in negative emotions. Higher self-compassion ratings were correlated with greater emotion regulation effect, particularly in adolescents with depression. Furthermore, LPP amplitudes were significantly higher in adolescents with depression than in healthy controls during both regulation and non-regulation conditions. Conclusions: Adolescents with depression were characterized by impairment in using self-compassion to downregulate negative emotions when confronted with social exclusion. LPP amplitudes were consistently elevated in adolescents with depression, underscoring their potential as a critical focus for psychophysiologically-informed therapies.

neuroscience↗

bioRxiv2026

Before auxin distribution matters: Prepatterning of the Arabidopsis embryo axis by MPK6-dependent AUX/IAA8 phosphorylation

In growth and development of plants, the signaling molecule auxin plays an instrumental role. Many patterning processes are controlled by auxin signaling in a self-organizing matter. After fertilization, such a patterning process needs to be started for the first time during plant life. Contrary to previous models, we show that the first differential auxin response that separates embryonic from extra-embryonic development in the two zygotic daughter cells happens independently of a detectable auxin gradient. Instead, differential phosphorylation of the transcriptional inhibitor Aux/IAA8 by MAP kinase signaling leads to differences in auxin sensitivity between the two daughter cells, initiating embryonic development in the apical cell. IAA8 phosphorylation in the basal cell prevents proteasomal degradation, suppressing canonical auxin responses, which initiates extra-embryonic development. MAP kinase signaling therefore precedes auxin gradients and prepatterns the apical-basal axis independently of an auxin gradient.

plant biology↗

bioRxiv2026

Multiplex Genome Editing Overcomes Photoperiod Sensitivity in Tropical Maize

Tropical maize is a rich source of genetic diversity that could enhance temperate maize breeding programs, but its sensitivity to long-day photoperiods, resulting in delayed flowering, limits its widespread use. To overcome this barrier, the Genome Engineering to Sustain Crop Improvement (GETSCI) project used CRISPR/Cas9 to mutate three flowering repressor genes, ZmCCT9, ZmCCT10, and ZmRAP2.7, in the tropical inbred Tzi8. A single sgRNA targeting the first exon of each target gene was combined with an excision cassette carrying the morphogenic genes Babyboom (Bbm) and Wuschel2 (Wus2) to enable efficient transgenic plant regeneration. Transgenic plants carrying frameshift edits in each target gene were recovered, and subsequent crosses produced two non-transgenic genotypes: a double-edited zmcct10, zmrap2.7 line and a triple-edited zmcct9, zmcct10, zmrap2.7 line. Multiple flowering traits were measured for the edited genotypes and unedited Tzi8 inbred in short-day (Hawai i) and long-day (Iowa) field conditions. Both edited genotypes flowered significantly earlier than Tzi8 in both environments. Notably, under long-day conditions, flowering of the two edited lines overlapped with that of the temperate inbred B73, whereas Tzi8 did not. Together, these results demonstrate that targeted, multiplex gene editing can reduce photoperiod sensitivity in a tropical inbred, expanding access to previously untapped genetic diversity for temperate maize improvement.

plant biology↗

bioRxiv2026

A durably colonizing engineered native symbiont enables sustained intestinal delivery for metabolic dysfunction and colitis

BackgroundEngineered bacterial therapeutics represent a promising strategy for sustained intestinal delivery of therapeutic molecules, but their efficacy is limited by inefficient colonisation, safety concerns and the need for repeated administration or auxiliary delivery systems. ObjectiveTo develop a safety-optimised native bacterial chassis capable of long-term gut colonisation and sustained therapeutic delivery for intestinal inflammatory and metabolic diseases. DesignNative murine Escherichia coli isolates were screened for antibiotic susceptibility, genetic tractability and long-term intestinal colonisation. The selected strain, MEc30, was further optimised by deleting the putative virulence-associated clb and irp loci. MEc30 was then engineered to deliver murine interleukin-10 (MEc30-mIL-10) or produce nicotinic acid (MEc30-NA), and therapeutic efficacy was evaluated in Il10-/- colitis and high-fat diet-induced metabolic dysfunction models. ResultsMEc30 achieved stable lifelong colonisation of the murine intestine after a single oral administration, without antibiotic preconditioning or auxiliary delivery systems, and did not detectably disturb host physiology or gut microbial ecology. Deletion of clb and irp abolished potential colibactin- and yersiniabactin-associated biosafety risks while preserving bacterial growth and colonisation capacity. MEc30-NA continuously produced nicotinic acid in the gut, activated epithelial GPR109a-associated barrier signalling, improved glucose and lipid metabolism, reduced systemic inflammation and avoided the sharp peak exposure associated with conventional nicotinic acid administration. MEc30-mIL-10 enabled sustained intestinal IL-10 delivery, suppressed inflammatory macrophage activation, improved barrier integrity and alleviated spontaneous colitis in Il10-/- mice. ConclusionThis study identifies MEc30 as a durable and safety-optimised native E. coli chassis for sustained intestinal therapeutic delivery. Engineered native symbionts may provide a long-acting live biotherapeutic strategy for chronic intestinal inflammatory and metabolic diseases.

microbiology↗

bioRxiv2026

Targeting NAT10 suppresses TFH responses and alleviates allergic asthma via an ac4C-TOX2 axis

Chemical modifications of RNA, such as N4-acetylcytidine (acC), fine-tune gene expression, but their roles in cell fate determination within the immune system remain poorly understood. Here, we identify the RNA cytidine acetyltransferase NAT10 as a pivotal regulator of T follicular helper (TFH) cell differentiation and the germinal centre response. T cell-specific ablation of Nat10 in mice severely impaired TFH cell development, germinal centre formation, and antibody production following viral infection. Integrated epitranscriptomic and transcriptional profiling revealed that NAT10 deposits acC modifications on a cohort of mRNAs critical for immune function. We pinpointed the transcription factor TOX2 as a key downstream target, showing that acC modification within its mRNA coding sequence enhances both transcript stability and translation efficiency, thereby promoting TOX2 protein expression. Enforced TOX2 expression fully rescued the TFH differentiation defect in NAT10-deficient cells. This NAT10-acC-TOX2 axis is conserved in humans, where its activity correlates with the magnitude of vaccine-elicited TFH responses. Furthermore, we identified R428 as a potent NAT10 inhibitor and demonstrated that its administration could suppress pathogenic TFH responses and alleviate symptoms in a mouse model of allergic asthma. Our work elucidates a central epitranscriptomic mechanism controlling T helper cell fate and humoral immunity, and nominates NAT10 as a potential therapeutic target for TFH-driven diseases.

immunology↗

bioRxiv2026

pHaseMD4AI: Phase-Space Dynamics Dataset with Chemical and pH Perturbations for Physically and Kinetically Consistent Biomolecular AI

Protein function emerges from dynamic conformational ensembles and transitions that are challenging to characterize experimentally and computationally. Recent advances in generative AI have created new opportunities for learning molecular thermodynamics, kinetics, and conformational evolution directly from simulation data, but progress is limited by the availability of large-scale datasets that combine rigorous sampling, complete phase-space information, and diverse physicochemical perturbations. Here, we present pHaseMD4AI, a molecular dynamics dataset that combines a globally equilibrated peptide branch with a protein-scale constant-pH molecular dynamics (CpHMD) branch spanning hundreds of soluble proteins. The peptide branch includes a complete set of canonical tripeptide and tetrapeptide systems together with post-translationally modified (PTM) and protonation-state datasets, providing synchronized atomic coordinates (R), velocities (V), forces (F), and Markov state model-based kinetic annotations. An accompanying web portal (https://isb.zju.edu.cn/md4ai/) enables users to browse, visualize, and download trajectories, annotations, and metadata. As an example application, we demonstrate a sequence-based model that can predict residue-level equilibrium dihedral distributions from sequence. pHaseMD4AI provides a resource for developing and benchmarking molecular machine learning methods while supporting broader studies of biomolecular dynamics under sequence, post-translational modification, and protonation-state perturbations.

bioinformatics↗

bioRxiv2026

Deep learning representations of human Immune Health for precision immunology

The human immune system is composed of [~]30-50 distinct cell types, each of which can exist in different states of activation or differentiation. Indeed, the mammalian immune system has evolved to sense and respond to infections, cancers, injuries, and changes in tissue or host homeostasis (1). Moreover, an increasingly large fraction of approved drugs target the immune system directly, and/or cause immune changes (2-4). A key feature of the immune system is to store some of this information, for example as innate or adaptive immune memory (5). In addition, rewiring of immune network architecture induced by disease, environmental exposures, drug treatments, and/or chronological age allows the immune system to store information in the pattern of connections and activity across populations of immune cells. This ensemble information storage, in addition to changes to individual cells, functions as a major way the immune system encodes aspects of immune history and future potential. Genetic information can identify inherited risk alleles, but cannot capture the continual remodeling of the immune system shaped by exposures, infection, inflammation, therapy, and aging (6, 7). To define and use such ensemble immunotypes, we developed a self-supervised deep learning framework that transforms high-dimensional immune profiles into representations of immune health. MAESTRO (MAsked Encoding Set TRansformer with self-distillatiOn) encodes a set of cells from an individual into an embedding that captures immune cell population-level organization. Pretrained on 1,792 peripheral blood samples comprising over 418 million immune cells across 13 clinical diagnoses, MAESTRO learns immune fingerprints that are stable within individuals yet diverse across populations, states of health, disease, and treatment, providing a quantitative basis for comparing immune states across individuals and over time. These fingerprints capture immune architecture beyond coarse cell type proportions, enabling patient-efficient clinical prediction using simple task specific models. MAESTRO model embeddings retain a temporal dimension of immune history and potential, reflecting signatures of past exposures and baseline features that predict future immune responses. Finally, we demonstrate a translational precision immunotherapy application by testing this approach in metastatic Pancreatic Ductal Adenocarcinoma (PDAC), where pretreatment immune landscape circuitry maps enable patient stratification and therapeutic response prediction. Overall, we developed a large, attention-based model that captures deep network architecture of immune states through self- supervised representations of immune cytometry data as a reusable foundation for precision immunology, converting immune complexity into clinically actionable embeddings for diagnosis, monitoring, and therapy selection.

immunology↗

bioRxiv2026

Distributed resonant coupling enables high efficiency power transfer to mm-scale bioelectronics

Miniaturized implantable bioelectronics offer breakthrough potential in disease treatment, biomarker monitoring, and physiological sensing. However, wireless power transfer (WPT) remains a central limitation for millimeter-scale devices, as scaling down the receiver size rapidly decreases coupling efficiency due to tissue attenuation, low quality-factors, reduced mutual inductance, and limited tolerance to spatial and angular displacement. Here, we introduce distributed resonant coupling (DRC), a 3-coil WPT paradigm which enables the receiver (Rx) to actively participate in a strongly coupled resonance, transforming the Rx from a passive energy harvester into an active participant in a strongly coupled regime. By co-designing transmitters (Tx), resonators (Rs), and mm-scale receiver coils (Rx) as fully coupled systems, DRC exhibits simulated maximum power levels of 66%, measured received power transfer efficiencies of [~]56%, and end-to-end DC power transfer efficiencies of 42%, delivering >420 mW to loads at 1 W of transmitted power while maintaining robust performance across a range of practically relevant orientations and tissue media. Systematic theoretical and experimental efforts establish core design rules for DRC systems enabling operation without specialized tuning integrated circuits or components. To illustrate the capabilities of DRC in practical applications in vivo, we demonstrate three technologies that capture a broad application space in bioelectronics: implant localization, rapid wireless battery charging, and ultraminiaturized drug delivery devices compatible with particulate drug formulations. Taken together, these results suggest operational capabilities across a wide range of angular tolerances (up to 60{degrees}), tissue depths and dielectric and scattering media.

bioengineering↗

bioRxiv2026

Curved microtubule regions mark sites of lattice compaction in cells and neurons

Angstrom-scale changes in microtubule (MT) lattice spacing regulate the selective recruitment of MT-associated proteins, yet how these structural states operate in cells remains poorly understood. Here, we show that MT lattice expansion, induced by protein-based expanders or microtubule-stabilizing agents such as Taxol and epothilone D, drives the relocalization of compact lattice-binding proteins, including tau, doublecortin (DCX), and the C1 domain-containing signaling protein GEF-H1, into highly curved MT-associated domains, whereas the compaction-inducing agent laulimalide suppresses this response. In contrast, the tumor suppressor RASSF1A preferentially associates with expanded lattice states, revealing differential lattice sensitivity among closely related C1 domain-containing proteins. These short, curved assemblies are enriched at MT intersections and discrete MT segments, revealing spatially heterogeneous lattice states within individual microtubules. At substoichiometric levels, compact lattice-binding proteins behave as both MT compactors and curvature sensors. Changes in osmotic pressure selectively promote dissociation of compact lattice-binding proteins, whereas expanded lattice-binding proteins remain largely unaffected. Using curved filament formation as an in-cellulo readout of compact lattice regions, we identify widespread lattice-state sensitivity across diverse MT-associated and signaling proteins. Finally, we show that these principles extend to neurons, where somatic, but not axonal, tau exhibits sensitivity to lattice expansion despite the expanded lattice architecture of distal axonal microtubules, suggesting additional neuron-specific regulation of lattice accessibility. Together, our findings identify the MT lattice as a dynamic mechanochemical platform whose nanoscale structural states spatially organize protein recruitment and signaling in cells and neurons.

cell biology↗

bioRxiv2026

Acoustic Characteristics of Low-Frequency Vocalizations of Bryde's Whales (Balaenoptera edeni edeni) in the Weizhou Island Waters of the Beibu Gulf, China

Brydes whales (Balaenoptera edeni edeni) are nationally protected in China, and the waters around Weizhou Island in the Beibu Gulf support one of the countrys few regularly observed coastal groups. However, acoustic data for this population remain limited, and the potential effects of local vessel noise are poorly described. We conducted 16 vessel-based surveys around Weizhou Island and adjacent waters in January 2024 using a low-disturbance sailboat platform and passive acoustic recorders, with concurrent visual observations where possible. We identified 734 low-frequency signals classified as putative Brydes whale vocalizations and quantified their temporal and spectral parameters. Call duration was significantly negatively correlated with maximum frequency and center frequency, but not with minimum frequency or bandwidth. Comparisons with published records indicate that the recorded signals are most similar to vocalizations previously reported from juvenile Brydes whales or mother-calf pairs, although individual source attribution could not be confirmed. Speedboat passage significantly increased root-mean-square sound pressure levels, and the dominant noise band overlapped the frequency range of the recorded Brydes whale signals, indicating potential for acoustic masking. These results expand the bioacoustic baseline for Brydes whales in Chinese coastal waters and provide evidence relevant to the management of vessel activity and whale-watching tourism around Weizhou Island.

animal behavior and cognition↗

bioRxiv2026

Controlled microtrauma opens a regenerative window for appendage-bearing skin repair

Adult skin normally resolves injury through rapid closure and fibrotic matrix deposition, often at the cost of permanent appendage loss. We tested whether spatially controlled microtrauma could instead serve as a regenerative entry point when paired with temporally coordinated molecular cues. We engineered a hierarchical extracellular-matrix-based microneedle patch that combines rapid local availability of verteporfin, an inhibitor of YAP-associated mechanotransduction, with sustained retinoic-acid delivery to support follicle-regenerative signalling. The microneedle interface was evaluated in full-thickness rabbit ear wounds, which are prone to hypertrophic scarring, and in Bama miniature-pig wounds, whose skin architecture more closely resembles human skin. Across both models, staged dual-cue treatment accelerated wound closure, reduced collagen-dense scar formation and promoted the appearance of hair-bearing tissue and histologically identifiable follicular structures. These findings support a trauma-guided regeneration framework in which controlled microinjury is used not only for delivery but also to open a transient repair niche that can be molecularly redirected toward appendage-bearing skin restoration. ImportanceMicroneedles are generally treated as minimally invasive delivery devices. Here, the microinjury itself is incorporated into the therapeutic design. The study provides cross-species proof of concept that a patterned injury interface, combined with staged anti-fibrotic and pro-regenerative signalling, can shift wound repair away from fibrotic closure and toward hair-follicle-containing skin. This concise preprint reports the central concept and the rabbit and porcine evidence supporting it; expanded mechanistic and source datasets will be reported separately.

bioengineering↗

bioRxiv2026

Orally available designed miniproteins inhibit enterotoxigenic Bacteroides fragilis pathology by blocking toxin receptor binding

Toxigenic bacterial infections in the gut are a significant contributor to the global burden of disease. Advanced tools for protein and live biotherapeutic engineering offer potentially transformative strategies for treating such diseases, while avoiding the collateral effects of traditional antibacterials. Here we used de novo protein design to identify inhibitors of the metzincin family protease Bacteroides fragilis toxin (BFT). These inhibitors, which bind distal to the active site, interfere with toxin-mediated E-cadherin cleavage and downstream proinflammatory signaling by blocking claudin-4 receptor binding. We tested the inhibitors as disulfide-stabilized variants administered directly to the cecum or in drinking water, as well as through in situ secretion by an engineered live biotherapeutic. Across these delivery modalities, the inhibitors successfully neutralized the toxin and effectively prevented BFT-associated gut pathology, including tumor formation. These results highlight the potential of de novo designed proteins as precise, non-antibiotic interventions to mitigate bacterial toxin-driven disease in the gut.

microbiology↗

bioRxiv2026

circPMS1-mediated LIM protein scaffolding promotes cytoskeletal remodeling and melanoma metastasis

Circular RNAs (circRNAs) have been implicated in diverse biological processes and diseases such as cancer; however, their functional roles in tumor biology remain incompletely understood. Here, we identify circPMS1 as an aberrantly upregulated, pro-metastatic circRNA in melanoma. Overexpression and silencing studies revealed that circPMS1 promotes migration and invasion of non-transformed melanocytes and melanoma cells, enhances metastasis in xenograft models, and drives spontaneous dissemination and lymph node metastases in a genetically engineered melanoma mouse model. circPMS1 pro-metastatic activity depends on its circularization and is mediated by a putative secondary structure spanning the back-splice junction and the canonical start codon of the linear PMS1 mRNA. Proteomic analysis identified LIM domain proteins, including ABLIM1, LMO7, and PDLIM7, as circPMS1-bound factors. Mechanistic studies demonstrate that circPMS1 scaffolds these LIM proteins, enhancing their association with actin filaments inducing focal adhesion and cytoskeletal remodeling. This remodeling is associated with RhoA activity, and inhibition of the RhoA pathway attenuates circPMS1-induced migration. Together, these findings establish circPMS1 as a pro-metastatic circRNA that drives melanoma progression by scaffolding LIM domain proteins and regulating cytoskeletal dynamics and cell motility.

Cancer Biology↗

bioRxiv2026

Persistent Post-Inflammatory Matrix Stiffening Defines a Premalignant Mechanical Niche in Ulcerative Colitis-Associated Neoplasia

Patients with long-standing ulcerative colitis (UC) remain at risk for colorectal neoplasia even after overt inflammatory activity improves, suggesting that repaired mucosa may retain residual tissue-level abnormalities. Whether extracellular matrix remodeling leaves a persistent mechanical cue that contributes to early neoplastic remodeling is unknown. Here we identify post-inflammatory matrix stiffening as a premalignant mechanical niche in UC-associated neoplasia. In human colonic biopsies, collagen remodeling and atomic-force-microscopy-based mucosal stiffness increased from non-UC controls to UC and UC-associated dysplasia. A stiffness-associated transcriptional program was also enriched in histologically non-dysplastic mucosa from patients with UC-associated neoplasia. In mouse models, colonic stiffness increased along the colitis-to-tumorigenesis axis and remained elevated during apparent recovery, when epithelial permeability, junctional protein loss, crypt proliferation and nuclear {beta}-catenin accumulation persisted despite reduced disease activity. Stiffness-controlled intestinal epithelial cultures showed that stiff substrates were sufficient to disrupt ZO-1 organization and enhance {beta}-catenin redistribution, particularly under TNF- stimulation. Pharmacological matrix normalization with {beta}-aminopropionitrile partially restored barrier organization and attenuated early epithelial remodeling in vivo. Single-cell profiling identified a stiffness-associated MMP7-positive/YAP-active epithelial state that was enriched in collagen-rich regions and reduced after matrix softening. Inhibition of YAP or MMP7 attenuated stiffness-associated junctional disruption and {beta}-catenin redistribution. These findings suggest that inflammatory recovery and mechanical recovery can be uncoupled, and that persistent mucosal stiffening provides a tissue-level mechanism by which chronically injured UC mucosa may remain biologically vulnerable to premalignant epithelial remodeling.

Cancer Biology↗

bioRxiv2026

Proteomic profiling of drug and nutrient transporter expression by small intestinal region in neonates, pediatrics, and adults

Transporters localized to the small intestinal epithelium govern the absorption of many orally administered drugs and nutrients, and thorough characterization of transporter protein abundance is key to accurate prediction of small molecule absorption. Previous studies have reported more than 100 solute carrier and ATP-binding cassette superfamilies expressed in the intestine, but only a small subset of these transporter proteins have been quantified in native intestinal tissue. In addition, a majority of published transporter abundance data for the intestine was collected with adult tissue. Here, we report the identification and relative quantification of 87 solute carrier and 18 ATP-binding cassette superfamily transporters by intestinal region in neonatal, pediatric, and adult small intestinal mucosa using data-independent acquisition mass spectrometry. This study identified transporters uniquely expressed by intestinal region in all three age groups and region-associated abundance for 23 SLC/ABC transporters in pediatrics and adults. The protein abundance data reported here provide a valuable resource for the prediction of nutrient and drug absorption and efflux across age and will inform future studies of specific transporters and age-associated differences in transporter abundance. Significance statementWe report the relative abundance of key xenobiotic transporters along the length of the small intestine in neonates, pediatrics, and adults based on data-independent acquisition mass spectrometry. Intestinal region-associated transporter expression was observed for drug transporters and under-studied nutrient transporters across age groups.

pharmacology and toxicology↗

bioRxiv2026

Reinforcement learning-driven unified generative framework for multi-objective RNA codon design

Current RNA codon design methods are limited by inefficient long-sequence processing and poor generalizability, often relying on a decoupled generate-or-optimize paradigm. We introduce RNARL, a reinforcement learning-driven framework that unifies sequence generation with multi-objective optimization. RNARL directly learns to generate high-performance sequences, effectively optimizing sequences over 3,900 nucleotides and demonstrating superior performance and universality across six species and five RNA types. RNARL thus establishes an effective and generalizable framework for RNA codon design. Finally, a user-friendly web platform is freely available to facilitate its application for RNA therapeutic design.

bioinformatics↗

bioRxiv2026

Accurate de novo design of peptides from programming biophysical landscape

Peptides regulate virtually every cellular process and emerge as transformative modalities in bioengineering and therapeutics. However, the de novo design of functional peptides remains challenging, as peptide-protein interactions are governed by delicate and dynamic biophysics that are difficult to model, and experimental datasets are scarce. Here we present NeoPep, a generative deep-learning framework that encodes biophysical principles to accurately design functional peptides de novo. By integrating over 5 million peptide-protein complexes spanning experimentally determined, sequence mimics, and structure ensembles, NeoPep learns the complex biophysical landscape governing peptide function and enables its programmable control. In prospective application across 10 diverse and challenging targets, NeoPep generated potent peptide binders, agonists, and antagonists with hit rates of 12.5-66.7%, even in the absence of defined binding sites or structure information. Beyond de novo co-design, NeoPep supports standalone structure or sequence redesign, readily discriminating subtle context differences. In the structure redesign mode, it generates highly selective peptides with atomic-level conformational accuracy (C RMSD < 2.0 [A] to our solved cryo-EM structure). This structural precision circumvents the need for experimental structure determination, further accelerating iterative sequence redesign to yield a 43.3-fold improvement in potency. These findings establish a general framework for translating biophysical principles into actionable peptide functions, with broad implications for basic research, bioengineering, and medicine.

molecular biology↗

bioRxiv2026

Miniaturized subcutaneous cellular implants for sustained therapeutic protein delivery in resource-limited settings

Cell encapsulation offers a promising strategy for sustained therapeutic protein delivery, obviating the need for repeated injections. Among potential implantation sites, the subcutaneous space is particularly attractive for its accessibility and amenability to minimally invasive procedures. However, performance of subcutaneous devices reported to date has been limited due to various challenges including foreign body response (FBR) and inadequate mass transfer. Moreover, typical encapsulation devices require surgeries for implantation and retrieval, limiting their potential use in resource-limited settings. Here we present a miniaturized cell encapsulation platform comprising cells engineered to produce therapeutic proteins and an FBR-mitigating zwitterionic polyurethane nanofibrous membrane, in a thin cylindrical form factor compatible with applicator-based minimally invasive implantation and retrieval. Clonal mesenchymal stromal cells engineered to produce PGT121, a broadly neutralizing anti-HIV-1 antibody, were encapsulated and inserted subcutaneously, achieving long-term cell survival and sustained serum PGT121 concentrations for up to 36 weeks across multiple murine models. Cell-loaded devices retained therapeutic function after cryopreservation, supporting their potential use as an off-the-shelf product that can be centrally manufactured and implanted on-site without specialized infrastructure. The custom-designed applicator-based implantation and minimally invasive retrieval procedures were demonstrated in a more clinically relevant minipig model. These mini-"cellular factories" represent a translatable strategy for sustained delivery of biologic drugs in resource-limited settings. One Sentence SummaryAn insertable and retrievable mini cellular construct enables sustained protein delivery, supporting its potential use in resource-limited settings.

bioengineering↗