Background/Objectives: Blood–brain barrier (BBB) permeability and cardiac hERG liability share physicochemical determinants, motivating the hypothesis that multi-task learning could improve BBB prediction. Methods: We tested this hypothesis using B3DB logBB regression (n = 1058) and a curated hERG dataset (n = 8960). A shared-encoder multi-task neural network was compared with a matched single-task network and Bayesian-optimized gradient boosting under ten random splits, 30 Murcko scaffold splits, and held-out classification sets. Results: Multi-task learning did not improve random-split R2 (0.485 ± 0.016 vs. 0.482 ± 0.015). Under scaffold splitting, its mean R2 was higher (−0.054 vs. −0.817) only because its failures were less severe (the same number of partitions had negative R2); medians were nearly identical (0.394 vs. 0.398). Neither loss weighting, network tuning, nor removal of 39.6% of test compounds sharing a parent structure with hERG training data changed this. Gradient boosting was more robust (scaffold R2 = 0.388 ± 0.188; better in 28–29 of 30 partitions), although not significantly so under a dependence-corrected test. Conclusions: Network failures occurred only when a scaffold group containing 18 atypical compounds (e.g., xenon) entered the test set; after removing 20 such compounds, multi-task R2 (0.409) matched gradient boosting (0.420). On 3031 held-out parent structures, AUCs were similar (0.764–0.772).
Background/Objectives: Acute pancreatitis (AP) is a common inflammatory disorder associated with substantial morbidity, mortality, and healthcare burden, particularly in patients with systemic inflammatory response syndrome (SIRS), pancreatic necrosis, and multiple organ dysfunction syndrome (MODS). Despite advances in intensive care management, nutritional support, and minimally invasive interventions, effective pharmacological therapies targeting the underlying inflammatory and enzymatic mechanisms remain limited. Protease activation, excessive inflammation, and immune dysregulation are key drivers of AP progression. Ulinastatin, a broad-spectrum serine protease inhibitor, exerts anti-inflammatory, antioxidant, and organ-protective effects by modulating protease activity, NF-κB signaling, cytokine production, and inflammasome activation. However, conventional intravenous administration is limited by rapid systemic clearance, nonspecific distribution, and insufficient drug exposure at sites of pancreatic inflammation, necessitating repeated dosing. This narrative review aims to evaluate the scientific rationale and the therapeutic potential of ulinastatin-loaded erythrocyte-based drug delivery systems as an innovative strategy for improving the efficacy of acute pancreatitis therapy by optimizing the sustained anti-inflammatory effect of ulinastatin in foci of pancreatic inflammation. Methods: Qualitative narrative synthesis of relevant experimental and clinical literature on AP pathogenesis, ulinastatin pharmacology and therapy, protease inhibition, erythrocyte ghosts, erythrocyte pharmacocytes, and erythrocyte-based drug delivery systems was critically reviewed. The analysis focused on evidence relevant to pancreatic inflammation, drug-delivery performance, potential therapeutic benefits, and translational limitations. Results: Available evidence supports the pharmacological relevance of ulinastatin in inflammatory and protease-mediated conditions and identifies erythrocyte-derived carriers as a potential platform for drug encapsulation, prolonged circulation, and controlled drug release. Direct experimental studies investigating ulinastatin-loaded erythrocyte pharmacocytes in AP are currently lacking. Conclusions: By combining the pharmacological properties of ulinastatin with the physiological advantages of erythrocyte-mediated drug delivery, this approach may offer potential therapeutic benefits. However, these potential advantages remain hypothetical and require validation through dedicated pharmaceutical characterization, pharmacokinetic, biodistribution, and efficacy studies. Ulinastatin-loaded erythrocyte pharmacocytes represent a scientifically plausible but currently unvalidated drug delivery strategy for AP. This narrative review critically examines the therapeutic rationale for combining ulinastatin with erythrocyte-derived drug carriers as a potential targeted delivery strategy for acute pancreatitis. It synthesizes relevant evidence on ulinastatin pharmacology, erythrocyte-based drug delivery, inflammatory mechanisms, and the limitations of conventional systemic administration. Particular attention is given to the potential advantages, translational challenges, and key research gaps associated with this proposed approach. Further preclinical studies are warranted to comprehensively evaluate their pharmacokinetic properties, biological activity, safety, therapeutic efficacy, and potential for clinical translation.
Covalent organic frameworks (COFs) have attracted growing interest as drug delivery platforms owing to their ordered porosity, tunable pore architecture, and versatile chemical functionality. Favorable physicochemical characteristics alone, however, do not guarantee effective performance in vivo, and biomimetic membrane engineering has emerged as a strategy for modifying the biological interface of COF nanocarriers. This review develops a principle-based framework structured around five interconnected concepts: biological identity transfer, functional mimicry, homotypic targeting, biophysical compatibility, and programmable responsiveness. Rather than treating membrane coating as a universally beneficial modification, it examines how far these functions depend on membrane source, retained biomolecules, membrane orientation, coating quality, and the properties of the underlying framework. Ten primary membrane-engineered COF systems are compared quantitatively across framework chemistry, membrane source and coating method, particle characteristics, cargo loading, release behavior, biological model, pharmacokinetics, therapeutic outcomes, safety, and study limitations. Five membrane-engineering strategies are evaluated against defined fabrication, scalability, integrity, targeting, cost, and regulatory criteria, distinguishing throughout evidence obtained directly in COF systems from findings extrapolated from other nanocarriers. Translational barriers, including donor variability, membrane integrity, immunogenicity, sterility, framework degradation, batch reproducibility, and regulatory requirements, are examined. Current evidence supports preclinical feasibility but not established translational readiness.
Background/Objectives: Surface chemistry is a major determinant of nanoparticle–cell interactions, yet their influence on mechanobiological properties of cells remains incompletely understood. This study investigated the cytotoxic and mechanobiological effects of thiolated and PEGylated organosilica nanoparticles and evaluated whether cortical stiffness could serve as a complementary measure of nanoparticle–cell interactions. Methods: We evaluated thiolated organosilica nanoparticles (Si NP-SH) and two PEGylated nanoparticles (Si NP-PEG750 and Si NP-PEG5000) in non-cancerous human pulmonary fibroblasts (HPF) and cancerous human pulmonary adenocarcinoma (A549) cells. We assessed cellular viability and nanoparticle uptake after exposure and used atomic force microscopy to measure cellular cortical stiffness. Additionally, nanoparticle effects on neuroblast proliferation and mitotic progression were examined in Drosophila melanogaster larval brain explants. Results: HPF cells were markedly less sensitive to all nanoparticle formulations across the tested concentration range, whereas A549 cells showed dose-dependent sensitivity, with thiolated nanoparticles producing the earliest and greatest reduction in viability. Despite a comparable uptake of Si NP-SH and Si NP-PEG750, the thiolated nanoparticles produced greater toxicity, whereas Si NP-PEG5000 showed lower uptake but intermediate toxicity. Atomic force microscopy measurements demonstrated significant cortical softening in Si NP-SH-treated A549 cells, while HPF cells were unaffected. All nanoparticles reduced Drosophila melanogaster neuroblast proliferation in a similar order: Si NP-SH > Si NP-PEG750 > Si NP-PEG5000. Conclusions: The biological activity of organosilica nanoparticles is predominantly dependent on accessibility and intracellular reactivity of surface thiols rather than uptake alone. PEGylation shields thiol reactivity, with higher PEG molecular weight additionally reducing nanoparticle uptake. The consistency of viability, uptake, cortical stiffness, and neuroblast proliferation identifies AFM-derived cortical stiffness as a valuable complementary measurement of nanoparticle-induced stress.
Oral exposure to lipophilic plant bioactives depends on lipid digestion and enterocyte handling. Long-chain fatty acids and monoacylglycerols can be re-esterified and assembled with apolipoprotein B48 into chylomicrons, creating a route through intestinal lymph that differs from portal delivery. Food-grade lipid nanocarriers may alter this pathway by changing lipid digestion, micellar solubilization, cellular uptake, and chylomicron secretion, yet evidence for lymphatic transport is often inferred from bioaccessibility or plasma exposure rather than measured directly. This review evaluates how triglyceride chain length, unsaturation, lipid physical state, emulsifier interfaces, food matrices, and processing shape the digestive transformation of nanoemulsions and lipid particles into mixed colloids and substrates for enterocyte lipid processing. It compares nanoemulsions, nanostructured lipid carriers, liposomes, and related systems, with attention to the distinction between intact-particle uptake and cargo incorporation into endogenous lipoproteins. Static and dynamic digestion, epithelial models, lymph-duct cannulation, chylomicron-associated analyte measurements, and human pharmacokinetics are considered as distinct evidence tiers. The synthesis identifies which design claims are supported by direct lymph measurements and which remain mechanistic hypotheses. A framework aligns lipid composition and cargo chemistry with the intended portal or lymphatic exposure pathway. By treating endogenous chylomicron assembly as a testable design target, this review distinguishes a route-specific mechanism from gains in solubilization, epithelial uptake, or plasma exposure alone.
