Mol. Pharm. [JOURNAL]
Sun
200 papers
Photodynamic Therapeutic Monitoring of Glioblastoma Using High-Resolution Photoacoustic Vascular Imaging.
He S, Zeng S, Zhang Y … +7 more , Sun M, Cao J, Ren Y, Liu C, Zhang L, Chen J, Sun L
Mol Pharm · 2026 Mar · PMID 41665364 · Publisher ↗
Glioblastoma multiforme (GBM) is highly angiogenic, which promotes its growth and invasion. Photodynamic effects not only kill tumor cells but also disrupt or seal the tumor blood vessels. Targeting strategies that integ...
Glioblastoma multiforme (GBM) is highly angiogenic, which promotes its growth and invasion. Photodynamic effects not only kill tumor cells but also disrupt or seal the tumor blood vessels. Targeting strategies that integrate effective tumor photodynamic therapy (PDT) with imaging-based vessel monitoring could lead to improvement in the diagnosis and treatment of GBM. Herein, we developed a biomimetic photosensitizer using a macrophage membrane hybrid lipid as the carrier of chlorin e6 to form a nanocomposite (MLCNPs). The MLCNPs demonstrated good biocompatibility and targeted GBM cells. Under laser irradiation, the MLCNPs showed significant photodynamic effects, which induced massive cell apoptosis. The targeting ability and PDT effect were investigated in an orthotopic glioma mouse model. During PDT in vivo, high-resolution photoacoustic (PA) imaging was used to monitor changes in the structure and function of the tumor vasculature. MLCNPs combined with high-resolution PA imaging provide a new strategy for GBM tumor diagnosis, treatment, and monitoring.
Engineering Goat Milk-Derived Extracellular Vesicles for Dual-Model Imaging and Anti-Inflammatory Photothermal Therapy of Pancreatic Cancer.
Gao Y, Jing B, Song W … +7 more , Song Y, Guo R, Qian R, Zhu Z, Yang B, Lan X, An R
Mol Pharm · 2026 Mar · PMID 41665203 · Publisher ↗
As an emerging modality for treatment, photothermal therapy demonstrates significant potential for clinical application. However, the inflammatory reaction after photothermal therapy can lead to tumor recurrence and meta...
As an emerging modality for treatment, photothermal therapy demonstrates significant potential for clinical application. However, the inflammatory reaction after photothermal therapy can lead to tumor recurrence and metastasis. As a novel photothermal agent, biliverdin (BV) also demonstrates a remarkable anti-inflammatory effect. In this study, goat milk-derived extracellular vesicles (GEVs) is used to encapsulate BV. The objective was to enhance tumor uptake of the photothermal agent while alleviating the inflammatory responses associated with photothermal therapy, thereby achieving superior therapeutic outcomes. N-GEV@BV was successfully synthesized. Additionally, it exhibited notable efficacy in photothermal therapy and demonstrated anti-inflammatory effects in vitro. Utilizing a pretargeting strategy, N-GEV@BV can accomplish PET/CT imaging in both subcutaneous and orthotopic tumor models. After photothermal treatment, the tumor volume in the N-GEV@BV+laser group exhibited a significant decrease relative to the other groups, with reductions of up to 1/13 observed. Furthermore, compared to N-GEV@ICG, mice injected with N-GEV@BV exhibited lower expression levels of inflammatory factors in both the serum and tumor tissues. As an integrated nanoprobe for diagnosis and treatment, N-GEV@BV can successfully mediate the photothermal therapy of tumor tissue. Notably, it contributes to enhanced tumor prognosis by mitigating the inflammatory response induced by photothermal therapy, underscoring its broad potential for application.
Solubility of Incongruently Melting Active Pharmaceutical Ingredient Cocrystals: The Hydrochlorothiazide-Nicotinamide System.
Nasrallah S, Gavali T, Yavuz I … +1 more , Minceva M
Mol Pharm · 2026 Mar · PMID 41664448 · Full text
Pharmaceutical cocrystallization is a promising strategy to enhance the solubility and bioavailability of hydrophobic active pharmaceutical ingredients (APIs). However, when API-coformer cocrystals exhibit incongruent me...
Pharmaceutical cocrystallization is a promising strategy to enhance the solubility and bioavailability of hydrophobic active pharmaceutical ingredients (APIs). However, when API-coformer cocrystals exhibit incongruent melting, understanding and predicting their solubility in water becomes significantly more complex. In this work, a combined experimental and thermodynamic modeling approach is presented to investigate the API solubility enhancement in a ternary API-coformer-water system. Hydrochlorothiazide (HCT), a biopharmaceutics classification system (BCS) class IV diuretic, and nicotinamide (Nic), a generally recognized as safe (GRAS)-listed coformer, were selected as a representative system that forms an incongruently melting 1:1 cocrystal, which was confirmed experimentally using differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Binary solid-liquid equilibrium (SLE) data for the HCT-Nic, HCT-water, and Nic-water systems were experimentally measured at different temperatures. The nonrandom two-liquid (NRTL) model was then used to regress the binary interaction parameters from the binary SLE data. These parameters were then used to predict ternary SLE phase diagrams of the HCT-Nic-water system at 310.15 K, 330.15 K, and 350.15 K. The NRTL-modeled SLE diagrams revealed the key features of the ternary system, including the absence of cocrystal formation at 310.15 K and the emergence of a cocrystal phase region with incongruent dissolution behavior at elevated temperatures. The highest HCT solubility was obtained at the ternary API-rich eutectic composition, with a solubility enhancement factor (Φ) of 2.1-2.4 across the studied temperatures. In contrast, dissolving the 1:1 cocrystal directly in water yielded significantly lower solubility enhancements (Φ ≈ 1.0-1.3). These findings clearly demonstrate that selecting a binary HCT-Nic mixture that, upon dilution in water, reaches the eutectic composition in the ternary HCT-Nic-water system yields greater solubility enhancement than starting from the cocrystal composition. This study emphasizes the importance of thermodynamic modeling in understanding solubility behavior and guiding the rational design of cocrystal-based pharmaceutical formulations, especially for API-coformer systems exhibiting incongruent melting.
Hotspot Interactions between Two Fab Molecules in Molecular Dynamics Simulations Improve Predictive Models of Aggregation Kinetics.
Wang Y, Williams HD, Dikicioglu D … +1 more , Dalby PA
Mol Pharm · 2026 Mar · PMID 41663055 · Full text
Protein-protein interactions (PPIs) are fundamental to numerous biological processes, and the identification of interaction hotspots is essential for understanding the mechanisms of protein aggregation and informing prot...
Protein-protein interactions (PPIs) are fundamental to numerous biological processes, and the identification of interaction hotspots is essential for understanding the mechanisms of protein aggregation and informing protein engineering efforts. Although various algorithms have been developed to predict hotspot regions for protein-protein interactions, little research has focused on understanding the relative roles of these largely protein surface-based interactions and the interactions between cross-β sheet-forming aggregation-prone regions (APRs) that are largely buried within proteins. This study uses all-atom molecular dynamics (MD) simulations to investigate the interactions between two Fab antibody fragments, focusing on the identification and characterization of the key interaction sites. Through frequency contact map analysis and principal component analysis, we identified specific residues that consistently formed stable contacts, distinguishing them from transient random interactions. Our findings revealed that while numerous contact points occurred throughout the simulations, relatively few sites acted as persistent hotspots based on the duration of their contacts. Comparison to single Fab simulations highlighted the influence of interfragment interactions on conformational dynamics. Inclusion of solvent accessibility for two surface hotspots, alongside one predicted APR, significantly improved models for predicting aggregation kinetics over 49 formulation conditions. The molecular-level insights gained will be important for guiding protein engineering strategies aimed at modulating these interactions to enhance product stability and retain therapeutic efficacy.
pH-Responsive Resveratrol Liposomes Targeting Sigma1 Receptor Attenuate Renal Fibrosis by Remodeling the Renal Microenvironment.
Yang N, Song Y, Song J … +4 more , Qin J, Fu M, Yao F, Xu H
Mol Pharm · 2026 Mar · PMID 41660892 · Publisher ↗
Renal fibrosis (RF), a critical pathogenic mechanism in chronic kidney disease (CKD), now has exceedingly few therapeutic alternatives. This study presents a new sigma1 receptor (σ1R)-targeted nanodelivery system utilizi...
Renal fibrosis (RF), a critical pathogenic mechanism in chronic kidney disease (CKD), now has exceedingly few therapeutic alternatives. This study presents a new sigma1 receptor (σ1R)-targeted nanodelivery system utilizing the natural polyphenolic medicine resveratrol (Res) as a therapeutic agent, addressing its low bioavailability and inadequate targeting properties, thereby providing a significant advancement in the treatment of RF. We engineered and produced a multifunctional material, aminoethyl anisamide-poly(2-ethyl-2-oxazoline)-cholesterol hemisuccinate (APC)-with benefits including active targeting, prolonged circulation, and pH sensitivity. investigations demonstrated that in the high glucose-induced HK-2 cell fibrosis model, the absorption efficiency of APC-modified liposomes was markedly enhanced, effectively suppressing the expression of fibrotic and inflammatory factors. In two typical animal models of RF, namely diabetic nephropathy and glomerulonephritis, APC@Res demonstrated therapeutic advantages, including modulation of the TGF-β1/Smad3 signaling pathway to impede fibrosis, a notable reduction in oxidative stress levels, enhanced renal function parameters, and diminished expression of inflammatory and fibrotic markers. This study innovatively employs the renal microacidic environment and sigma1 targeting to develop an effective delivery system, offering a novel treatment strategy for reversing RF.
Tracking MAPK-Dependent CD38 Upregulation by All-Trans Retinoic Acid in Human Leukemia Using Zr Immuno-PET.
Kim M, Koo HJ, Jung KH … +4 more , Kim JL, Kim G, Lee H, Lee KH
Mol Pharm · 2026 Mar · PMID 41653422 · Publisher ↗
Anti-CD38 antibodies (Abs) are promising immunotherapeutics for hematologic malignancies, but their efficacy in leukemias often requires pharmacologic upregulation of CD38. Immuno-PET provides a noninvasive strategy to e...
Anti-CD38 antibodies (Abs) are promising immunotherapeutics for hematologic malignancies, but their efficacy in leukemias often requires pharmacologic upregulation of CD38. Immuno-PET provides a noninvasive strategy to evaluate such target modulation in vivo. Cysteine site-specific Zr labeling of anti-CD38 Abs was performed using deferoxamine-maleimide. CD38-specific target binding was confirmed in three human myeloma and two leukemia cell lines. Total and surface expressed CD38 levels were assessed by Western blotting and flow cytometry. Immuno-PET imaging and biodistribution studies were conducted in murine leukemia models. All-trans retinoic acid (ATRA) was used to stimulate CD38 expression. Myeloma and MOLT4 leukemia cells showed variable baseline CD38, while HL60 cells exhibited negligible levels. All tumor cells demonstrated Zr-OKT10 IgG and Zr-daratumumab (Fc-silenced) binding that paralleled surface CD38 expression. ATRA upregulated CD38 in all tested cells, including a marked induction in HL60 cells, all accompanied by corresponding elevations in Zr-CD38 Ab binding. On Zr-OKT10 IgG PET, MOLT4 tumors showed high uptake that was reduced by 67.9% with unlabeled Ab, but HL60 tumors showed low uptake and high liver accumulation, limiting ATRA assessment. Zr-daratumumab produced lower liver uptake and improved MOLT4 and HL60 tumor visualization; ATRA modestly increased MOLT4 tumor uptake and substantially enhanced HL60 tumor uptake from 8.0 ± 1.7 %ID/g to 14.7 ± 3.1 %ID/g (83.8% increase; < 0.005). Mechanistic studies demonstrated ATRA-induced ERK1/2 activation in HL60 cells that was abolished by the MAPK inhibitor U0126; U0126 also suppressed CD38 induction and Zr-CD38 Ab uptakes in all tested tumor cells. Furthermore, U0126 blocked ATRA-induced HL60 tumor Zr-daratumumab uptake in vivo. Western blots and immunohistochemistry confirmed ATRA-induced HL60 tumor CD38 elevation, which was partly reversed by U0126. Thus, Zr immuno-PET enables noninvasive monitoring of ATRA-driven CD38 upregulation via MAPK signaling and supports its potential utility for optimizing combination strategies in leukemias.
Zn-Driven Tavaborole-Adenosine Hydrogel: A Strategy for Enhanced Solubility, Sustained Release, and Antifungal Efficacy.
Sun Y, Sha H, Lei C … +5 more , Zhi F, Hu N, Song C, Qiao R, Li C
Mol Pharm · 2026 Mar · PMID 41653137 · Publisher ↗
Onychomycosis is a common fungal nail infection, causing nail thickening and discoloration. Tavaborole, a topical antifungal, has fewer side effects but requires long treatment periods and often results in low cure rates...
Onychomycosis is a common fungal nail infection, causing nail thickening and discoloration. Tavaborole, a topical antifungal, has fewer side effects but requires long treatment periods and often results in low cure rates. In this study, we developed a Zn-driven tavaborole-adenosine (AT-Zn) hydrogel to improve its therapeutic effect. The hydrogel enhanced tavaborole's solubility, drug loading, and antifungal activity. Characterization by nuclear magnetic resonance (NMR), ultraviolet-visible (UV-vis) spectroscopy, and transmission electron microscopy (TEM) confirmed its successful synthesis and nanofiber structure. In vitro release tests showed that about 65% of tavaborole was released in PBS at pH 5.5 over 24 h, indicating pH-sensitive drug release for targeted therapy. Permeation studies using a bovine hoof model showed effective tavaborole penetration through keratinized tissues with a steady-state flux of 162 μg/cm/h. The AT-Zn hydrogel demonstrated lower minimum inhibitory concentrations (MICs) for (0.00156 mM) and (0.025 mM) compared to those of tavaborole alone. In a bovine onychomycosis model, the hydrogel showed stronger antifungal effects than the tavaborole solution. Cytotoxicity assays on RAW 264.7 cells indicated good biocompatibility with >85% cell viability. These findings suggest that the AT-Zn hydrogel holds significant potential as a clinically effective antifungal agent.
Microstructural Insights into Solid Dispersions: A Combined Small-Angle Neutron Scattering and Molecular Dynamics Approach.
Gao H, Zhang Y, Jiang H … +4 more , He C, Ke Y, Li H, Ouyang D
Mol Pharm · 2026 Apr · PMID 41653134 · Full text
Solid dispersion is a widely adopted formulation strategy to enhance the solubility of water-insoluble drugs. However, the molecular-level structural determinants of stability and dissolution behavior remain poorly under...
Solid dispersion is a widely adopted formulation strategy to enhance the solubility of water-insoluble drugs. However, the molecular-level structural determinants of stability and dissolution behavior remain poorly understood. This study integrates Small-Angle Neutron Scattering (SANS) technology with coarse-grained molecular dynamics (CGMD) simulations to investigate the effects of preparation methods (melting vs solvent evaporation) and drug loadings (10%, 15%, 25%) on the microstructure and crystallinity of PXM-PEG solid dispersions. Deuterated PEG (d-PEG) is used in the SANS to enhance the scattering intensity in samples. The findings revealed that the lamellar thickness decreased significantly from 173.01 Å (pure d-PEG) to 44.12 Å (25% drug loading, melting method), while the -spacing reduced from 71.13 to 36.65 Å, indicating a substantial disruption of the crystalline structure. Conversely, samples prepared by solvent evaporation maintained larger -spacing (up to 93.27 Å at 10% drug loading) and more stable layer stacking (Nlayers ∼5.6), demonstrating higher structural order. The results indicate that the preparation method significantly influences the structural characteristics of the solid dispersions. The melting method yielded a higher amorphous content at low drug loadings, which is expected to improve drug solubility and bioavailability. In contrast, the solvent evaporation method tended to produce solid dispersions with higher crystallinity and uniform structures at higher drug loadings. SANS results indicated that samples prepared by the melting method exhibited higher disorder in the high- region, while those prepared by the solvent evaporation method showed greater crystallinity. The CGMD simulations further elucidated the dynamic aggregation and structural formation of the drug and polymer molecules during the preparation process. In the melting simulations, drug and polymer molecules gradually aggregated into dense clusters, while in the solvent evaporation simulations, the aggregates grew larger and more asymmetrical as the solvent evaporated, ultimately forming ordered structures. The combined results from SANS and molecular dynamics simulations indicated the "sandwich-like" structure of PXM-PEG solid dispersions. The outcomes of this innovative approach have the potential to advance the development of solid dispersion formulations, enhance research and development efficiency, and pave the way for the industrial production of solid dispersions.
A Two Birds with One Stone Strategy: Sialic Acid-Modified Pitavastatin Liposomes for Combating Atherosclerosis and Tumors.
Lu S, Wang S, Tang X … +5 more , Gui Y, Lian J, Liu X, Song Y, Deng Y
Mol Pharm · 2026 Mar · PMID 41649341 · Publisher ↗
Atherosclerotic cardiovascular disease (ASCVD) poses a severe threat to human health, and the global prevalence of atherosclerosis-related diseases continues to rise, necessitating urgent exploration of novel strategies....
Atherosclerotic cardiovascular disease (ASCVD) poses a severe threat to human health, and the global prevalence of atherosclerosis-related diseases continues to rise, necessitating urgent exploration of novel strategies. Inspired by the close links between tumors and atherosclerosis (AS), as well as the clinical reality of their comorbidity, the present study encapsulated pitavastatin within liposomes and modified them with sialic acid-cholesterol (SA-CH) to achieve targeted drug delivery via peripheral blood neutrophils (PBNs). Compared to oral pitavastatin administration, sialic acid-modified pitavastatin liposomes (PIT-SAL) demonstrated superior efficacy in attenuating disease progression in atherosclerotic mice, with sustained therapeutic effects even after treatment cessation, suggesting the potential for eradication of AS. Notably, PIT-SAL additionally exhibited antitumor potential by effectively reducing tumoral cholesterol accumulation while enhancing T-cell infiltration. Collectively, our preliminary findings highlight the great translational potential of PIT-SAL as a targeted therapy for both AS and tumors, offering a potential breakthrough in managing these interconnected diseases.
[Ga]Ga-PG2-2FAPI: A DPro-Gly-Modified Dimeric FAPI Probe with Enhanced Tumor Uptake and Retention.
Ruan Q, Jiang Y, Li Z … +7 more , Duan X, Diao L, Ding D, Han P, Yin G, Jiang J, Zhang J
Mol Pharm · 2026 Mar · PMID 41648948 · Publisher ↗
In this study, a novel fibroblast activation protein (FAP) targeting ligand based on the bivalent DPro-Gly structure, DOTA-PG2-2FAPI, was designed and synthesized. Molecular docking analysis revealed that compared with m...
In this study, a novel fibroblast activation protein (FAP) targeting ligand based on the bivalent DPro-Gly structure, DOTA-PG2-2FAPI, was designed and synthesized. Molecular docking analysis revealed that compared with monomeric FAPI-46, DOTA-PG2-2FAPI had a higher binding score (-15.00 vs -11.36), with an IC value of 6.65 nM, indicating a significantly increased binding affinity toward FAP. The Ga-labeled complex ([Ga]Ga-PG2-2FAPI) demonstrated radiochemical purity exceeding 95% with good stability and high hydrophilicity (Log = -3.29 ± 0.06). In HT-1080-FAP cells, the cellular uptake of [Ga]Ga-PG2-2FAPI reached 10.98 ± 0.10% ID, which decreased by 92% upon FAP inhibition. studies using tumor-bearing mice revealed that the tumor uptake of [Ga]Ga-PG2-2FAPI was 17.60 ± 1.33% ID/g in HT-1080-FAP tumors and 32.71 ± 0.98% ID/g in U87MG tumors, which was significantly greater than that in nontargeted tissues. Positron emission tomography (PET) imaging revealed rapid tumor accumulation and sustained retention, with high-specificity imaging across all four tumor models (HT-1080-FAP, U87MG, HT-29, and PANC-1). On the basis of these characteristics, this probe holds promise as a broad-spectrum tumor imaging agent with significant clinical application value.
Correction to "Antimicrobial Peptides Expressed by the Polyaminoglycoside Nanosystem for Bacterial Peritonitis Management via Inflammation Modulation".
Ju R, Yu B, Sui D … +1 more , Xu FJ
Mol Pharm · 2026 Mar · PMID 41645609 · Publisher ↗
Abstract loading — click title to view on PubMed.
Impact of Silicone Oil and Storage Conditions on the Physicochemical and Functional Stability of mRNA-LNPs: The Critical Role of mRNA Structure.
Du CY, Gao H, Jia F … +2 more , Ding ZL, Fang WJ
Mol Pharm · 2026 Mar · PMID 41645492 · Publisher ↗
Lipid nanoparticles (LNPs) have emerged as a leading platform for mRNA delivery; however, their compatibility with prefilled syringes (PFS) containing silicone oil (SO) as a lubricant remains unexplored. This study inves...
Lipid nanoparticles (LNPs) have emerged as a leading platform for mRNA delivery; however, their compatibility with prefilled syringes (PFS) containing silicone oil (SO) as a lubricant remains unexplored. This study investigated the effects of SO on the physicochemical stability and biological activity of mRNA-LNPs under various storage conditions (4 °C, 25 °C, and light exposure). Using polyadenylic acid (Poly A) and enhanced green fluorescent protein-encoding mRNA (eGFP-mRNA) as models, we evaluated particle size, polydispersity index (PDI), zeta potential, encapsulation efficiency (EE%), and transfection efficacy. The results showed that Poly A-LNPs exhibited significant particle size increases and PDI changes at 25 °C with SO, whereas eGFP-LNPs maintained stability under the same conditions, probably because of the mRNA secondary structure enhancing colloidal stability. At 4 °C, both formulations remained stable for 12 weeks, but long-term storage led to a gradual EE reduction. Under light exposure, eGFP-LNPs retained a high EE but suffered severe mRNA degradation, resulting in a near-complete loss of transfection activity. Notably, SO partially mitigated light-induced damage, improving transfection efficiency by up to 6-fold in 100 ppm (ppm) SO-spiked samples. These findings reveal mRNA-dependent LNP-SO interactions and underscore the necessity of evaluating both the physicochemical and functional stability of PFS-based mRNA-LNP formulations.
Characterization of Storage-Induced mRNA Modifications in ()-KEL12 LNP: Adduct Formation Kinetics, mRNA Decay, and Translational Competence.
Chen H, Gong J, Wu W … +10 more , Shi Y, Li J, Yu Z, Bao H, Ye X, Zhang T, Dong Y, Cen S, Lv K, Zhang W
Mol Pharm · 2026 Mar · PMID 41637581 · Publisher ↗
Lipid-mRNA adducts form during storage for several types of lipid nanoparticles (LNPs) and impair therapeutic efficacy, yet their structural drivers and functional consequences remain incompletely characterized, especial...
Lipid-mRNA adducts form during storage for several types of lipid nanoparticles (LNPs) and impair therapeutic efficacy, yet their structural drivers and functional consequences remain incompletely characterized, especially for novel lipids with distinct structures. Here, we investigated adduct formation between mRNA and several impurities derived from an immunotropic ionizable lipid ()-KEL12, which has been used to develop therapeutic mRNA cancer vaccines approved for human clinical studies. Elevated storage temperatures promoted both adduct accumulation and the loss of mRNA integrity with divergent kinetics at 25 °C, suggesting their independence. Mechanistically, degradation impurities of ()-KEL12, particularly its aldehyde derivative (Z4) and N-oxide derivative (Z1) dominated adduct generation, with Z4 exhibiting ∼4-fold higher activity than Z1. Moreover, mRNA adduction with Z4 did not reduce mRNA integrity by capillary electrophoresis, further supporting independent pathways. Mass spectrometry characterization unambiguously identified cytidines as the primary target on mRNA for Z4 adduction. Functionally, while adducted mRNAs exhibited poor capacity for protein expression in cultured human 293T cells, they did not stimulate significant gene expression involved in innate immunity for RNA sensing and downstream type I interferon pathway activation in human THP1 cells. These findings not only clarify important functional consequences of adducted mRNAs, but also establish impurity control and thermal management as actionable strategies for advancing mRNA therapeutics.
Effect of Low Glucose on mRNA Delivery Efficiency via Lipid Nanoparticles and Its Underlying Mechanisms.
Hu Z, Shi L, Lin X … +9 more , Zhang Q, Zhang Y, You F, Chen J, Wang H, Ye Y, Chen J, Deng W, Deng G
Mol Pharm · 2026 Mar · PMID 41627893 · Publisher ↗
mRNA therapy has shown great potential in vaccine development, cancer treatment, and the treatment of rare diseases. Lipid nanoparticles (LNPs) are key delivery carriers that are essential to the success of mRNA therapy....
mRNA therapy has shown great potential in vaccine development, cancer treatment, and the treatment of rare diseases. Lipid nanoparticles (LNPs) are key delivery carriers that are essential to the success of mRNA therapy. Here, we found that a low-glucose microenvironment affected the efficiency of LNP-mediated mRNA delivery. Two LNPs (ALC-0315@LNP and SM-102@LNP) were tested in three types of cells under different glucose conditions. The results showed that low-glucose levels significantly reduced the translation of LNP-delivered mRNA into protein, and this negative effect was reversible upon the restoration of glucose levels. A mouse tumor model further confirmed that hypoglycemia diminished the mRNA delivery efficiency of LNPs. Further mechanistic studies revealed that the reduced efficiency was not due to impaired cellular uptake or lysosomal escape of LNPs, but rather to disrupted glucose energy metabolism. Under low-glucose conditions, cellular ATP and GTP levels were reduced, directly inhibiting the mRNA translation process, which is dependent on these high-energy molecules. This study systematically revealed for the first time that low-glucose conditions reduced mRNA-LNP delivery efficiency by impairing cellular energy metabolism. These findings provide insights for designing metabolic-microenvironment-adapted mRNA therapies and offer strategies to improve mRNA therapy efficacy in treating ischemic stroke and cancer patients.
Deciphering Copper Homeostasis and Cuproptosis: Biological Mechanisms, Disease Connections, and Cutting-Edge Copper-Based Nanomedicine.
Zhang SX, Li LG, Wang LJ … +4 more , Chen NN, Leng F, Xu HZ, Li TF
Mol Pharm · 2026 Mar · PMID 41627328 · Publisher ↗
Copper (Cu), as an essential trace element, participates in various physiological processes through strict homeostatic regulation. Abnormal intracellular copper accumulation can cause multiple forms of copper-dependent c...
Copper (Cu), as an essential trace element, participates in various physiological processes through strict homeostatic regulation. Abnormal intracellular copper accumulation can cause multiple forms of copper-dependent cell death (including apoptosis, autophagy, ferroptosis, and the recently identified cuproptosis) and disrupt cellular functions, which emphasizes the importance of maintaining copper homeostasis. This review aims to outline the connections between the copper homeostatic regulatory network and different copper-dependent cell death pathways, exploring their potential for understanding disease mechanisms and developing targeted therapies. Therefore, this review systematically discusses copper homeostasis, copper-related diseases, copper-dependent cell death, and the associated mitochondria-dependent mechanisms. Additionally, we highlight the implications of various copper-dependent cell death processes in diseases (such as Menkes disease, Wilson disease, neurodegenerative disorders, and cancer), as well as the potential role of copper-induced cellular proliferation (cuproplasia) in tumor progression. As our understanding of copper metabolism regulation deepens, strategies targeting copper-associated cell death, including copper-based nanobiomaterials and targeted drug delivery, show promise as emerging therapeutic approaches for multiple diseases. Future research should further elucidate the links between copper-dependent cell death and disease, not only to understand the underlying mechanisms but also to develop nanomedicine-based interventions, alongside assessments of the feasibility and safety of restoring copper homeostasis in clinical practice.
Ginseng-Derived Exosomes-Loaded Thermosensitive Hydrogel for the Treatment of Periodontitis.
Wang X, Yu Y, Li X … +3 more , Liu C, Lu Z, Wang Z
Mol Pharm · 2026 Mar · PMID 41628353 · Publisher ↗
Periodontitis represents a persistent inflammatory condition marked by the irreversible destruction of the alveolar bone, eventually leading to tooth loss. The ideal treatment for periodontitis involves three key steps:...
Periodontitis represents a persistent inflammatory condition marked by the irreversible destruction of the alveolar bone, eventually leading to tooth loss. The ideal treatment for periodontitis involves three key steps: antibacterial treatment, inflammation control, and periodontal regeneration, ultimately leading to the complete restoration of alveolar bone and the full recovery of periodontal function. However, current periodontitis treatments cannot comprehensively solve these issues. In this study, a ginseng-derived exosomes (GEXs)-loaded injectable hydrogel (GEXs@Gel) was designed. GEXs@Gel was thermosensitive with good fluidity, capable of conforming to the intricate contours of periodontal pockets, while withstanding the persistent wash of gingival crevicular fluid. In vitro studies showed that GEXs and GEXs@Gel can inhibit the growth of periodontal pathogenic bacteria, effectively remove biofilms, promote the polarization of macrophages to the anti-inflammatory (M2) phenotype, and alleviate cellular oxidative stress. In particular, GEXs@Gel had the functions of promoting bone/angiogenesis and regeneration. In vivo studies showed that GEXs@Gel effectively inhibited inflammation, promoted alveolar bone regeneration, and effectively reversed periodontitis. In summary, GEXs@Gel offers a promising strategy for the treatment of periodontitis.
Cascade Nanoreactor Based on MoC MXene for NIR-II-Activated Multimodal Therapy of Cancer.
Zhao L, Li J, Zhang X … +2 more , Bai Y, Feng F
Mol Pharm · 2026 Mar · PMID 41623258 · Publisher ↗
The complexity and dynamic nature of the tumor microenvironment (TME) pose significant challenges to effective cancer therapy. Therefore, the development of nanocomposites capable of fully exploiting TME characteristics...
The complexity and dynamic nature of the tumor microenvironment (TME) pose significant challenges to effective cancer therapy. Therefore, the development of nanocomposites capable of fully exploiting TME characteristics is crucial for achieving precise and efficient tumor treatment. Herein, the cascade nanoreactor PDA@MoC-MnO-Au/Apt-M (PMMAA) was successfully constructed based on MoC MXene and nanozymes. This nanoreactor leveraged the TME to achieve NIR-II-triggered combined photothermal therapy and chemodynamic therapy (PTT/CDT) with active targeting capability. PMMAA exhibited a photothermal conversion efficiency of 41.89% under NIR-II laser irradiation, enabling efficient thermal ablation of tumor tissues. In the acidic TME, the loaded MnO NPs mediated Fenton-like reactions that selectively converted endogenous HO into highly cytotoxic OH, realizing intelligent TME-responsive CDT. Notably, the embedded Au NPs in the nanoreactor exhibited glucose oxidase-like activity, catalyzing the conversion of glucose into HO and gluconic acid, thereby simultaneously elevating both HO levels and local acidity to establish a self-amplifying catalytic cascade. This nanozymes-based cascade amplification effect significantly enhanced CDT efficacy by promoting OH generation. Systematic evaluations demonstrated that the nanoreactor possessed dual enzyme-mimicking activities (POD-like and GOx-like), excellent biosafety, and remarkable tumor suppression effects. This study established a new paradigm for precision cancer therapy through the rational design of multifunctional nanozymes-enhanced CDT capable of dynamically modulating the TME.
Surface Activity Changes after Photoirradiation of PS80 in Citrate Buffer Containing Iron and Disulfide.
Escobar ELN, Ke G, Zhang Y … +3 more , Abdelsalam E, Schöneich C, Dhar P
Mol Pharm · 2026 Mar · PMID 41623089 · Publisher ↗
Polysorbate 80 (PS80) is a commonly used surfactant for stabilizing biotherapeutics by preventing protein adsorption at the air-liquid interface. However, PS80 is susceptible to oxidative degradation during manufacturing...
Polysorbate 80 (PS80) is a commonly used surfactant for stabilizing biotherapeutics by preventing protein adsorption at the air-liquid interface. However, PS80 is susceptible to oxidative degradation during manufacturing and storage. We show here that light exposure combined with the presence of metals can result in byproduct formation and potentially decrease the surfactant's ability to prevent protein adsorption to the air-liquid interface. PS80 formulated in citrate buffer can undergo isomerization of unsaturated fatty acids in the presence of disulfides and iron (Prajapati et al., 2022). This work investigates novel surface activity aspects of polysorbate formulations before and after exposure to UV-A light. Polysorbate samples of different grades were formulated in citrate buffer containing iron and glutathione disulfide (GSSG; as a surrogate for peptide and protein disulfides), and a Langmuir trough was used to monitor the surface pressure during adsorption to the air-solution interface. Our results showed significant changes in the polysorbate surface activity after photoirradiation: all-oleate PS80 exhibited a 3-fold increase in the apparent critical micelle concentration (CMC), and the presence of both and fatty acids was confirmed. Also, the impact of photoirradiation on surface pressure depended on the surfactant concentration during irradiation, suggesting that the presence of micelles can alter the degradation pathway and byproduct formation.
Microbubbles for Acoustically Mediated Drug Delivery to the Inner Ear.
Jeanneau C, Micaletti F, Fouan D … +5 more , Schubnel V, Chauvierre C, Galvin JJ, Escoffre JM, Bakhos D
Mol Pharm · 2026 Mar · PMID 41622949 · Publisher ↗
The blood-labyrinth barrier (BLB) is a selective endothelial barrier that maintains the homeostasis of the inner ear and protects it against toxic molecules and pathogens. This highly selective barrier represents a signi...
The blood-labyrinth barrier (BLB) is a selective endothelial barrier that maintains the homeostasis of the inner ear and protects it against toxic molecules and pathogens. This highly selective barrier represents a significant challenge for the delivery of therapeutic agents to the inner ear. To overcome this issue, various drug delivery methods have been developed. Among these modalities, microbubble-assisted ultrasound is an innovative and promising method for the noninvasive, targeted and efficient delivery of therapeutic agents through the round window membrane. The safety and the efficacy of this physical modality is strongly dependent on physiological properties of the targeted tissue, the pharmacological properties of the therapeutic molecules, the ultrasound parameters but also microbubble-related properties. The present review focuses on the current state of MB formulations and their use for the acoustically mediated inner ear drug delivery.
Developing Nanotechnology for Intratumoral Immunotherapy.
Omole AO, Cai H, Fiering S … +1 more , Steinmetz NF
Mol Pharm · 2026 Feb · PMID 41622896 · Publisher ↗
Abstract loading — click title to view on PubMed.
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