The high interfacial energy of nanomaterials limits their certain biomedical applications that require stealthiness to minimize non-specific interaction with biological components. While steric repulsion-based entropic stabilization—such as PEGylation—has long been the dominant strategy for designing stealth nanomaterials, its inherent softness and susceptibility to dynamic deformation and external forces often result in only moderate stealth performance. Here we report a distinct approach to achieving stealthiness by harnessing an ion-pair network, rather than maximizing steric repulsion. Using model polyion complex nanoparticles composed of equimolar charge ratios of polycations and polyanions, we demonstrate that increasing crosslinks between the constituent polyions beyond a critical threshold effectively reduces protein adsorption and macrophage uptake, enabling prolonged circulation with a half-life exceeding 100 hours. Building on this, we develop an asparaginase-loaded vesicular nanoreactor enveloped by a semi-permeable ion-pair network sheath for asparagine starvation therapy. The extended circulation of these nanoreactors enables sustained depletion of asparagine, leading to improved therapeutic outcomes for metastatic breast and pancreatic cancers. Our findings open an avenue for improving the pharmacokinetics of nanomaterials for therapeutic delivery through delicately engineering stable intermolecular structures with holistic cooperativity. A vesicular nanoreactor has increased crosslinks between the constituent polyions for longer blood circulation, and is shown to sensitize solid tumours to asparagine starvation therapy.

Neutron capture therapy (NCT) stands as a transformative approach for precision oncology. The principle relies on tumor‐targeted isotopes, such as boron‐10 ( 10 B) and gadolinium‐157 ( 157 Gd), for generating cytotoxic high energy particles upon thermal neutron irradiation. Compared to 10 B‐based NCT (BNCT), 157 Gd offer unparalleled neutron capture cross‐section and MRI contrast capability, positioning it as a next‐generation theranostic candidate. Here, we developed hybrid polymeric‐gadolinium oxide core–shell nanoparticles (Gd 2 O 3 NPs) as an NCT platform. The Gd 2 O 3 NPs were synthesized from a series of poly(ethylene glycol)‐poly( L ‐aspartic acid) (PEG‐PAsp) block copolymers, aiming to optimize their biocompatibility, pharmacokinetics and tumor‐targeting capability. Suitable Gd 2 O 3 NP formulations showed sub‐100 nm size and excellent colloidal stability. Moreover, the Gd 2 O 3 NPs offered higher Gd loading and minimal Gd 3+ release. In a model of intractable pancreatic cancer, the Gd 2 O 3 NPs based on PEG‐PAsp having a PEG segment of 12 kDa and 20 Asp units exhibited highest therapeutic efficacy while maintaining systemic safety. This promising performance positions the Gd 2 O 3 NPs for further preclinical evaluation toward effective NCT treatments.

Background/Objectives: Discriminating bacterial from mammalian membranes remains a central challenge in antibiotic design. Bacterial membranes are enriched in phosphatidylethanolamine (PE), a lipid normally absent from the outer leaflet of mammalian cells, providing a signature for selective molecular engagement. We report a compact covalent ligand, 6-dimethylamino-4-ketohexanoic acid (DMAX), which targets PE via Schiff base formation, leveraging its tertiary amine to facilitate the reaction and strengthen ionic binding with the phosphate group. Methods: The reactivity of DMAX and PE was evaluated by computational simulations, and their interaction was examined by spectroscopic analyses (NMR and FT-IR) and an artificial membrane assay. The targeting ability of DMAX for live bacteria was determined by microscopy study, and its applicability to therapeutic system was tested in vitro under washed conditions that mimic rapid in vivo clearance. Results: Spectrometric analyses revealed the selective covalent interaction of DMAX and PE, consistent with the simulated results. Fluorescently labeled DMAX selectively binds PE-enriched model membranes and efficiently recognizes Gram-negative bacteria while sparing mammalian cells. Conjugation of DMAX to Gemifloxacin (Gem) significantly enhanced antibiotic efficacy by 10-fold compared with free Gem, even after rapid drug clearance, while maintaining safety in mammalian cells. Conclusions: These results identify DMAX as an efficient and versatile PE-targeting platform, enabling selective membrane anchoring to advance precision antibiotic strategies.

Abstract Pregnant patients have limited treatment choices to ensure fetal safety as many drugs can breach the placental barrier. Nanomedicine has the potential to offer safe systemic treatments by precisely managing the drug distribution and activity. However, designing nanomedicines that avoid transport to the fetus is challenging, especially because of the differences in the placentas between species. To address this challenge, we investigated the permeability of the human placenta to various PEGylated nanoparticles, discovering a critical size threshold of 30 nm for fetal transport. Guided by this finding, we developed two types of PEGylated nanomedicines, i.e., anti-inflammatory agents for preterm birth prevention and cytotoxic treatments for cancer during pregnancy. In mouse models, these nanomedicines demonstrated therapeutic efficacy without crossing the placental barrier, ensuring fetal well-being. Our research establishes a foundation for safe and effective disease management during pregnancy via size-controlled nanomedicines, with high potential for clinical translation.

ABSTRACT Transgelin is an actin‐binding protein that promotes cancer progression via activation of cancer‐associated fibroblasts and has been identified as a prognostic marker. However, its distribution and functional role in colon cancer remain unclear. In this study, we aimed to elucidate the mechanistic role of transgelin in colon cancer progression by focusing on its functional impact in cancer‐associated fibroblasts. Tissue microarrays from 359 human colon cancer tissues were investigated to elucidate the clinical importance of transgelin expression in cancer stroma. We focused on transgelin in fibroblasts and investigated its functional role in stromal activation using in vitro knockdown experiments and in vivo co‐transplantation models. Primary cultures of human colon fibroblasts were evaluated for their biological function. Our data showed that transgelin expression is predominant in activated cancer‐associated fibroblasts in colon cancer tissues. Stimulation by cancer‐cell‐conditioned medium (CM) significantly upregulated transgelin, ACTA2, COL1A1, and TNC expression in colonic fibroblasts. Additionally, transgelin knockdown (KD) in fibroblasts did not influence the upregulation except for transgelin itself. Transgelin KD in fibroblasts did not result in drastic alterations in gene expression profiles. Transgelin KD suppressed collagen gel contractility. Furthermore, co‐transplantation experiments of cancer cells and colonic fibroblasts into immunodeficient mice revealed that transgelin KD inhibited tumor growth in fibroblasts. In conclusion, stromal transgelin expression in colon cancer strongly correlated with distant metastasis and served as a prognostic factor for colon cancer. Mechanistically, transgelin in cancer‐associated fibroblasts promotes tumor growth by regulating stromal contractility, suggesting transgelin as a potential therapeutic target.

Gut microbiota shapes nanomedicine fate by regulating hepatic clearance, with implications for tumour delivery.

Messenger RNA (mRNA)-based therapeutics hold great promise by enabling in situ expression of therapeutic proteins. The success of these therapies in vivo critically depends on the design of safe and efficient delivery systems. Polymeric micelles formed by block catiomers can encapsulate mRNA, protect it from degradation, and facilitate intracellular delivery. Polycation chain length has been proposed as a design parameter of micelles, yet how it governs stabilizing interactions to define mRNA delivery performance remains unestablished. Here, we systematically investigate this relationship using a series of poly(ethylene glycol)-poly(glycidyl-phenylalanate) (PEG-PG(Phe)) block copolymers with varying PG(Phe) chain lengths. These polymers interact with mRNA via polyion complexation and π-π stacking. Our findings revealed that the block catiomers having PG(Phe) segments with 90 units formed micelles with superior stability and enhanced endosomal escape, while micelles with shorter segments were rapidly dissociated and micelles with longer blocks showed impaired PEG shielding. Moreover, the polymer with a PG(Phe) block of 90 units achieved 2-fold higher protein expression in vivo compared to shorter or longer chain variants. These findings reveal that tuning polycation chain length with core π-π interactions is key to unlocking highly efficient mRNA delivery.

Rationale: Bone metastases - common in metastatic castration-resistant prostate cancer (mCRPC) - lead to severe complications and currently suffer from limited therapeutic options. Poor solubility, systemic toxicity, and therapeutic resistance hamper conventional approaches, such as docetaxel (Dtx) treatment. Nanomedicine-based strategies - including polymer-drug conjugates - can help overcome said limitations through enhanced tumor targeting and reduced unwanted side effects in healthy tissues. Methods: An intratibial bone mCRPC mouse model - used to recapitulate tumor growth and microenvironmental dynamics - was developed and characterized. A poly-L-glutamic acid (PGA)-Dtx) conjugate synthesized to enhance Dtx delivery and efficacy was also characterized in terms of size, zeta potential, drug loading, and pH-dependent release. In vivo evaluations included tumor growth monitoring by bioluminescence imaging, cathepsin K activity from tumor by fluorescence imaging, bone damage evaluation by micro-computed tomography, tumor vasculature by light-sheet fluorescent microscopy, cell population at tumor site by histology, modulation of blood cell populations by tumor and treatment by hematology, and biodistribution of PGA-Dtx using fluorescent imaging and intravital microscopy. Results: Our intratibial bone mCRPC model supported reliable tumor establishment, progressive osteolytic damage and vascularization, and systemic inflammation. PGA-Dtx displayed optimal properties (6.6 nm size, -24.1 mV zeta potential, 3.3 mol % drug loading) and supported lower but sustained Dtx release at acidic pH. The enhanced tumor accumulation following PGA-Dtx administration significantly suppressed tumor growth in vivo, normalized cathepsin K activity levels, and reduced bone damage while avoiding the systemic toxicity associated with free Dtx. Conclusions: Our intratibial bone mCRPC mouse model provides a robust platform for studying PCa bone metastases and evaluating nanomedicine efficacy. PGA-Dtx displays promise as a safe and effective therapy for mCRPC, offering improved drug delivery and reduced systemic side effects, which supports the translational potential of polymer-drug conjugates in mCRPC management.

Eukaryotic initiation factor 2 (EIF2) signaling plays a crucial role in regulating mRNA translation and initiating eukaryotic protein synthesis. Computational molecular network pathway analysis of the canonical pathways of the coronaviral infection revealed that EIF2 signaling is inactivated when the coronavirus pathogenesis pathway is activated and vice versa. Our computational analyses indicated that the coronavirus pathogenesis pathway and EIF2 signaling had inverse activation states. Computational investigation of upstream or downstream microRNA (miRNA) revealed that EIF2 signaling directly interacted with miRNAs, including let-7, miR-1292-3p (miRNAs with the seed CGCGCCC), miR-15, miR-34, miR-378, miR-493, miR-497, miR-7, miR-8, and MIRLET7. A total of 36 nodes, including 8 molecules (ATF4, BCL2, CCND1, DDIT3, EIF2A, EIF2AK3, EIF4E, and ERK1/2), 1 complex (the ribosomal 40s subunit), and 1 function (apoptosis) in the coronavirus pathogenesis pathway, overlapped with EIF2 signaling. Alterations in EIF2 signaling may play a role in the pathogenesis of coronavirus.

Metabolism dysregulation induces distinct thiol profiles between cancer and healthy cells, offering an attractive therapeutic target. However, systemically targeting cancer-specific thiols remains challenging due to the widespread presence of these groups in the physiological environment. Here, we design a molecular navigator (MONA) with spatiotemporally programmable thiol-reactivity to target the thiols on cancer cells upon intravenous injection. MONA operates through a bioresponsive "Hide-and-Seek" mechanism based on tunable disulfide exchange across biological compartments. In the “Hide” phase, MONA circulates stealthily through rapid conjugation with endogenous albumin via disulfide bonding. In the “Seek” phase, albumin facilitates MONA transcytosis into tumors, where elevated glutathione levels trigger disulfide exchange, releasing MONA to multivalently engage with thiols on cancer cells. When conjugated with a photosensitizer, MONA induces cancer cell membrane disruption upon light irradiation, enabling potent phototherapy. This approach leads to complete tumor regression and systemic abscopal effects in an immunosuppressive murine breast cancer model. These findings highlight MONA as a powerful strategy for precise thiol-targeted cancer therapy.

Polyion complex (PIC) vesicles are attractive carriers for mRNA delivery, yet their assembly is often compromised by charged cargos that disrupt the electrostatic interactions required for vesicle formation. Here, we report triblock polyampholyte vesicles (TBPVs) that encode preferential polymer-polymer interactions, enabling robust vesicle assembly independent of cargo-mediated disruption. Constructed from poly(ethylene glycol)-b-poly(L-lysine)-b-poly(aspartic acid) copolymers, TBPVs encapsulate both free mRNA and pre-condensed mRNA polyplexes while preserving vesicle integrity. Notably, the TBPVs encapsulating pre-condensed mRNA polyplexes demonstrated significant protein expression both in vitro and in vivo. Disulfide crosslinking of the vesicular membrane further confers stability under physiological conditions, while providing redox responsiveness for intracellular disassembly and cargo release. Systemically administered SS-TBPVs loaded with mRNA polyplexes enable detectable hepatic transgene expression in vivo. These findings support triblock polyampholyte PIC vesicles as a versatile and cargo-tolerant platform for polyplex-based nucleic acid delivery.

Injury causes resistance in human gastric cancer. Adverse Outcome Pathway (AOP) 298, entitled "increase in reactive oxygen species (ROS) leading to human treatment-resistant gastric cancer," consists of "increase in ROS" as a molecular initiating event (MIE), followed by a series of key events (KEs), namely "porcupine-induced Wnt secretion and Wnt signaling activation," "beta-catenin activation," and "epithelial-mesenchymal transition (EMT)," and the adverse outcome (AO) of "treatment-resistant gastric cancer" in the sequence. AOP 298 includes four KE relationships (KERs): "increase in ROS leads to porcupine-induced Wnt secretion and Wnt signaling activation," "porcupine-induced Wnt secretion and Wnt signaling activation leads to beta-catenin activation," "beta-catenin activation leads to EMT," and "EMT leads to treatment-resistant gastric cancer." ROS has multiple roles in disease, such as in the development and progression of cancer, or apoptotic induction, causing anti-tumor effects. Regarding AOP 298, we focus on the role of sustained chronic ROS levels in inducing therapy resistance in human gastric cancer. EMT, induced by Wnt/beta-catenin signaling, demonstrates cancer stem cell-like characteristics in human gastric cancer.

Pancreatic ductal adenocarcinoma (PDAC) features a fibrotic tumor microenvironment that impedes drug delivery and significantly limits the successful clinical application of nanomedicines. Targeting signaling in pancreatic stellate cells (PSCs), which drive fibrosis via excessive secretion of extracellular matrix proteins such as collagen I, may be useful in overcoming this fibrotic barrier. The AMPK‐related kinases NUAK1/2 have recently gained interest as promoters of fibrosis, but whether they play a profibrotic role in PSCs remains unknown. Here, patient PSCs are used to assess NUAK1/2 involvement in the PDAC fibrotic barrier. Leveraging a 3D cell culture model of PDAC fibrosis, the effect of targeting NUAK1/2 on the permeability of macromolecular dextrans of various sizes, as well as physiologically relevant macromolecules, albumin and IgG, and clinical nanomedicines, Doxil and Abraxane, is investigated. NUAK1/2 inhibition is shown to diminish collagen I to enhance macromolecular permeability, via a mechanism independent of established pathways involving transforming growth factor‐β (TGFβ) and yes‐associated protein (YAP). Through isoform‐specific knockdown, predominant NUAK2 involvement is demonstrated. Mechanistically, actin stress fiber regulation by NUAK2 is shown to be important. Altogether, these results show in vitro that NUAK2 promotes fibrotic signaling in PSCs and may be targeted to enhance macromolecular drug delivery in PDAC.

Neutron capture therapy (NCT) stands as a transformative approach for precision oncology. The principle relies on tumor-targeted isotopes, such as boron-10 (10B) and gadolinium-157 (157Gd), for generating cytotoxic high energy particles upon thermal neutron irradiation. Compared to 10B-based NCT (BNCT), 157Gd offer unparalleled neutron capture cross-section and MRI contrast capability, positioning it as a next-generation theranostic candidate. Here, we developed hybrid polymeric-gadolinium oxide core-shell nanoparticles (Gd2O3 NPs) as an NCT platform. The Gd2O3 NPs were synthesized from a series of poly(ethylene glycol)-poly(L-aspartic acid) (PEG-PAsp) block copolymers, aiming to optimize their biocompatibility, pharmacokinetics and tumor-targeting capability. Suitable Gd2O3 NP formulations showed sub-100 nm size and excellent colloidal stability. Moreover, the Gd2O3 NPs offered higher Gd loading and minimal Gd3+ release. In a model of intractable pancreatic cancer, the Gd2O3 NPs based on PEG-PAsp having a PEG segment of 12 kDa and 20 Asp units exhibited highest therapeutic efficacy while maintaining systemic safety. This promising performance positions the Gd2O3 NPs for further preclinical evaluation toward effective NCT treatments.

mRNA-based therapies hold immense potential for treating a plethora of diseases. However, their application to central nervous system (CNS) disorders remains limited due to biological barriers, such as rapid degradation in circulation, restricted brain access, and endosomal entrapment within cells. To address these challenges, we developed a polymeric micelle-based nanocarrier capable of systemically delivering mRNA to the brain. This system employed triphenylphosphonium (TPP) as a cationic moiety to stably complex with mRNA and prolong its blood circulation. TPP was introduced into a PEG-polyaspartamide derivative bearing diethylenetriamines, whose pH-responsive ionizable amines facilitated endosomal escape. For brain targeting, antibody fragments against transferrin receptor 1 were conjugated to the PEG shell at a controlled density via click chemistry. This rational, multifaceted design enabled robust in situ protein production in the brain following systemic administration, achieving around a 10-fold increase compared to our initial formulation, while exerting lower impact on off-target expression in other organs. Our system offers a promising platform for systemic mRNA delivery to the brain, opening new avenues for treating CNS disorders.

The coronavirus pathogenesis pathway, which consists of severe acute respiratory syndrome (SARS) coronavirus infection and signaling pathways, including the interferon pathway, the transforming growth factor beta pathway, the mitogen-activated protein kinase pathway, the apoptosis pathway, and the inflammation pathway, is activated upon coronaviral infection. An artificial intelligence approach based on machine learning was utilized to develop models with images of the coronavirus pathogenesis pathway to predict the activation states. Data on coronaviral infection held in a database were analyzed with Ingenuity Pathway Analysis (IPA), a network pathway analysis tool. Data related to SARS coronavirus 2 (SARS-CoV-2) were extracted from more than 100,000 analyses and datasets in the IPA database. A total of 27 analyses, including nine analyses of SARS-CoV-2-infected human-induced pluripotent stem cells (iPSCs) and iPSC-derived cardiomyocytes and fibroblasts, and a total of 22 analyses of SARS-CoV-2-infected lung adenocarcinoma (LUAD), were identified as being related to “human” and “SARS coronavirus 2” in the database. The coronavirus pathogenesis pathway was activated in SARS-CoV-2-infected iPSC-derived cells and LUAD cells. A prediction model was developed in Python 3.11 using images of the coronavirus pathogenesis pathway under different conditions. The prediction model of activation states of the coronavirus pathogenesis pathway may aid in treatment identification.

Bone marrow (BM) has roles in health and disease, so systemically administered nanocarriers (NCs) targeting or avoiding BM are desirable. While the hydrodynamic diameter of NCs can be tuned to target or avoid various organs, the size dependence of extravasation from BM vessels is unknown. To clarify the size dependence of passive transvascular transport in the BM, we performed vessel permeability measurements in murine calvaria using confocal fluorescent microscopy with fluorescently labeled dextrans, albumin, and polymeric micelles as model probes. Unexpectedly, we found the permeability of BM vessels to macromolecules decreases with increasing hydrodynamic diameter between 4 nm and 32 nm. We modeled this permeability data with mathematical models to predict an effective pore size for sinusoids of 47 nm and non-sinusoids of 37 nm, with estimated maximum pore sizes of 61 nm and 53 nm, respectively. Finally, we tested these model predictions by demonstrating that the extravasation of 70 nm polymeric micelles, which are larger than the estimated maximum pore size, is hindered relative to 30 nm polymeric micelles. These results establish design criteria for controlling NC hydrodynamic diameter towards modulating delivery to BM.