Human erythropoietin (hEPO) is the principal regulator of erythropoiesis and has been used therapeutically as recombinant hEPO (rhEPO) since 1989. Beyond this hematopoietic role, hEPO is also a tissue-protective cytokine with neurotrophic and neuroprotective activities. Clinically, rhEPO is widely used to treat anemia, although even in that setting its approved labeling carries boxed warnings for an increased risk of death, myocardial infarction, stroke, venous thromboembolism, vascular access thrombosis, and tumor progression or recurrence. Neuroprotective applications, however, require substantially higher and more frequent doses to overcome its limited blood–brain barrier permeability, and at these doses rhEPO produces dose-related adverse effects. Some of these, such as polycythemia and thrombotic events, are attributable to its erythropoietic activity, whereas others, including the excess mortality reported in acute ischemic stroke, remain mechanistically unexplained. This safety profile, together with the absence of benefit on the primary endpoint of three large randomized trials, is the main reason why rhEPO has not been approved for neurodegenerative disorders or neuronal tissue injury, and it has motivated the search for non-erythropoietic hEPO analogues. This review examines the dual biological functions of hEPO and their implications for biopharmaceutical innovation through two complementary cases originating from the Universidad Nacional del Litoral (UNL), Argentina. Zelltek emerged from academic research on recombinant glycoprotein production and developed a manufacturing platform for rhEPO, subsequently commercializing the product and contributing to the development of Argentina’s biopharmaceutical industry. BioSynaptica arose from research into the non-erythropoietic activities of hEPO and is advancing engineered, hyperglycosylated hEPO variants designed to dissociate erythropoietic activity from neuroprotective and other tissue-protective effects. Considered together, these university spin-offs illustrate two distinct translational trajectories arising from the biology of a single molecule: the industrial production of an established therapeutic protein and the preclinical development of engineered candidates targeting unmet medical needs. Their experiences also highlight the complementary roles of academic research, technology transfer, intellectual property, and sustained development efforts in translating biological discoveries into biopharmaceutical innovation.
Background: Multimodal pharmacogenomic models can use more biological information, but additional assays also increase cost, dimensionality, missingness, and integration complexity. It remains unclear whether copy-number and mutation data provide reliable improvement beyond an expression-only model when validation is organized around held-out drugs and response datasets. Methods: This study compared expression-only and early-fusion Ridge models using expression, copy-number, and damaging-mutation data from GDSC1, GDSC2, and CTD2 across a declared 15-compound benchmark. Feature selection, imputation, and scaling were performed within each training fold to limit leakage. Results: In five grouped drug-held-out splits, fusion achieved a mean RMSE of 0.2322 compared with 0.2328 for expression alone, an improvement of 0.0006; fusion performed better in four splits and worse in one. In leave-one-dataset-out validation, fusion was less favorable in all three source-held-out tests. Modality availability also differed substantially, particularly for copy-number data. Conclusions: These findings suggest that additional omics may provide a small benefit within a defined response system, but the benefit is variable and may not transfer across datasets. For early drug discovery and biomarker-model development, the results support retaining additional assays only when their incremental value is reproducible, their availability matches the intended population, and their benefit is confirmed by external validation. The study evaluates a cell-line-only model and therefore does not establish arbitrary new-drug prediction, clinical treatment selection, or causal biological effects.
Background/Objectives: Morin is the first flavonoid isolated from plants in the Moraceae family and has been reported to exhibit anticancer and antioxidant activity. It is classified as a Class IV compound in the Biopharmaceutical Classification System due to its low water solubility and low permeability. This study aimed to develop and characterize morin-loaded liposomes composed of DPPC and cholesterol to improve their stability and anticancer activity. Methods: Liposomes were prepared by thin-film hydration and then processed by bath sonication, probe sonication, or membrane extrusion to control vesicle size. Formulations were characterized by hydrodynamic diameter, polydispersity index (PDI), zeta potential, encapsulation efficiency (EE), and colloidal stability over 7 days at 37 °C. The cytotoxic effects of free and encapsulated morin were evaluated in tumor (MDA-MB-231, B16F10) and non-tumor (NIH-3T3, HEK-293T) cell lines. Results: Extrusion yielded the most homogeneous liposomes (PDI = 0.2, size ≈ 90 nm), whereas sonication methods produced larger, more polydisperse vesicles. EE ranged from 11–17%, with no significant differences among methods. Free morin degraded by 40% at 37 °C after 7 days, whereas liposomal encapsulation significantly reduced degradation, preserving 82–89% of the compound. At a morin equivalent of 3.4 µM, the bath-sonicated formulation reduced viability to approximately 65% in MDA-MB-231 cells and 70% in B16F10 cells, whereas viability remained approximately 86% in NIH-3T3 cells and 82% in HEK-293T cells. All formulations maintained colloidal stability over the study period. In cytotoxicity assays, free morin showed minimal activity, whereas liposomal formulations significantly enhanced antiproliferative effects against cancer cells. Conclusions: These findings demonstrate that DPPC/cholesterol liposomes effectively stabilize morin and improve its bioactivity, representing a promising strategy for delivering this flavonoid in anticancer therapies.
Protein therapeutics such as insulin, monoclonal antibodies, peptide hormones, cytokines, enzymes and vaccine antigens have revolutionized the treatment of chronic and complex diseases, but are currently constrained by adherence issues with frequent injection, cold-chain requirements and their intrinsic vulnerability to structural degradation. Dissolving microneedle (DMN) patches have recently been identified as a transdermal platform which allows minimally invasive, self-administered drug delivery and solid-state stabilization of fragile biologics. However, it is a significant challenge to keep the structural integrity and biological activity of proteins when developing the formulation, fabricating the microneedles, drying, storing the fabricates, and applying them to the skin. The mechanisms of molecular degradation (e.g., unfolding, aggregation, fibrillation, oxidation, deamidation, interface-induced denaturation) and stabilization (e.g., water replacement, vitrification, preferential hydration, and molecular confinement) all contribute to the stability of proteins in DMN matrices. Other processes also modulate these processes, such as polymer–protein interactions, residual moisture, glass-transition behavior, molecular mobility and microenvironmental physicochemical conditions. The rational engineering of polymer matrices, excipients systems and processing conditions therefore is the key to preserving a higher-order protein structure while providing sufficient mechanical properties, quick dissolution, higher drug loading efficiency and reproducible intradermal delivery. In recent years, a wide range of multifunctional biomaterials, hybrid polymer architectures, carrier-free insulin formulations and stimuli-responsive matrices have significantly broadened the design space for insulin and other biologic formulations that enables their stabilization during ambient and accelerated storage. Moreover, recent developments in biophysical characterization, solid-state analytical methods and computational modeling have helped to gain insight into formulation–structure–function relationships, and accelerated the rational optimization of protein-loaded DMN systems. Yet, there are still many difficulties to overcome for long-term stability, scalable manufacturing, quality-by-design implementation, regulatory standardization and global deployment. By combining mechanistic protein biophysics, pharmaceutical formulation and translational manufacturing, a platform for robust, cold-chain independent dissolving microneedles with a wide range of clinical applications across next-generation biologic therapeutics can be built.
Alzheimer’s disease (AD) presents a formidable therapeutic challenge due to the blood–brain barrier (BBB), which severely restricts central nervous system (CNS) access for systemically administered agents. Intranasal delivery offers a direct, non-invasive route to the brain parenchyma via olfactory and trigeminal pathways; however, its clinical efficacy is constrained by rapid mucociliary clearance and poor mucosal retention. While organic nanocarriers have been extensively reviewed, a critical knowledge gap remains regarding the dual diagnostic and therapeutic utility of inorganic nanosystems via the nose-to-brain route. This review specifically addresses this gap by analysing inorganic nanoscale platforms—including mesoporous silica, gold, silver, superparamagnetic iron oxide, quantum dots such as cadmium or carbon quantum dots and nanoceria—from a distinct theranostic perspective. We evaluate the key physicochemical parameters (surface chemistry, core morphology, and valence dynamics) that govern mucosal retention, epithelial transport, and brain bioavailability. Crucially, this review establishes a rigorous classification that explicitly distinguishes experimentally demonstrated theranostic platforms, concurrently integrating real-time bio-imaging with neuroprotective efficacy, from potential candidates that exploit therapeutic or diagnostic features in isolation. Furthermore, this work systematically details the parenchymal fate of inorganic platforms, focusing on pharmacokinetic bottlenecks, microglial sequestration, and glymphatic clearance dynamics. Recognizing that these advanced inorganic systems remain strictly within preclinical stages, we critically examine the translational landscape, outlining the key interspecies anatomical differences, chronic biopersistence constraints, and manufacturing scalability bottlenecks that currently impede clinical entry. By integrating recent toxicological constraints with green synthesis, Safety and Sustainability by Design (SSbD) frameworks and advanced surface engineering strategies, this review provides a dedicated framework for translating biocompatible, non-invasive inorganic theranostics into clinical applications for AD.
