Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal solid malignancies, and its therapeutic failure reflects both aggressive tumor-cell biology and the highly restrictive tumor microenvironment (TME). A defining hallmark of PDAC is desmoplasia, an extensive, extracellular matrix (ECM)-rich fibroinflammatory reaction that frequently exceeds the tumor cell compartment itself. Evidence from genetically engineered mouse models and human specimens identifies pancreatic stellate cells (PSCs) as the dominant architects of this stroma. Upon activation, PSCs differentiate into matrix-producing fibroblasts that drive collagen and hyaluronan (HA) accumulation, tissue stiffening, and vascular compression. ECM remodeling elevates interstitial pressure, collapses perfused vessels, and establishes profound hypoxia, which in turn reinforces fibroblast activation and matrix deposition through feed-forward signaling loops. These hypoxic, high-stress conditions severely restrict the delivery of cytotoxic agents, biologics, and nanomedicines, while simultaneously activating mechanotransduction pathways that enhance tumor cell survival under therapy. Clinical attempts to ablate stromal components validated the barrier function of desmoplasia but also revealed its tumor-restraining roles, exposing the limitations of indiscriminate depletion. This review synthesizes PSC-driven stromal initiation, matrix biomechanics, spatial zonation, and formulation-aware delivery into a single framework to explain why stromal targeting has repeatedly failed clinically and which normalization strategies are most likely to improve therapeutically effective exposure in PDAC.

Acute myeloid leukemia (AML) in older adults, particularly with mutation in the tumor suppressor gene TP53, has high rates of resistance to standard chemotherapy regimens, often resulting in patients’ death within months of diagnosis. To address this unmet need, we investigated the therapeutic potential of targeted nanoparticles (NPs) loaded with MDP5 (our novel BRD4/PI3K dual inhibitor) and azacitidine (AZA), a standard-of-care hypomethylating agent. A combination of MDP5 and AZA demonstrated synergistic inhibitory effects in both TP53 wild-type and TP53-mutant AML cell lines, and downregulated expression levels of MYC, BCL-2, and CDK6. To improve delivery, we developed a novel AZA-conjugated polymer, mPEG113-p(Asp-BLA)-p(Asp-AZA)-g-p(Asp-DA), which self-assembles into NPs. C-type lectin-like molecule-1 (CLL1) is highly expressed on leukemic blasts and leukemia stem cells (LSCs) but not universally across all AML subtypes. To leverage this selective targeting, we modified NPs with a peptide that recognizes CLL-1. The CLL-1 targeted NPs loaded with MDP5 and AZA demonstrated superior AML control and targeting of LSCs in TP53-mutant mice models, while sparing normal hematopoiesis in healthy NSG mice. These promising results highlight a potential efficacy of our novel CLL-1 targeted NP combination approach to treat AML, particularly those harboring TP53 mutation.

Oncology drug discovery remains limited by high attrition, slow experimental iteration and weak translation from preclinical models to clinical benefit. This review examines how AI is restructuring that process through three connected layers: biological foundation models that reduce uncertainty in molecular and cellular systems; generative design methods that improve candidate quality and compress medicinal chemistry cycles; and autonomous discovery platforms that integrate reasoning, experimentation and feedback. We analyze targeted protein degradation, emerging clinical validation and evolving regulatory frameworks; and argue that future progress will depend on causal inference, context generalization, interpretability and regulatory-grade evidence generation rather than model scale alone.

The blood-brain barrier (BBB) presents a critical challenge in treating central nervous system (CNS) disorders, particularly aggressive brain cancers such as glioblastoma (GBM) and medulloblastoma (MB). RNA therapies exploit endogenous cellular machinery to modulate gene expression, targeting previously undruggable pathways. RNA and CRISPR gene therapies hold transformative potential for brain cancer but demand breakthroughs for enhanced drug transport across the BBB. While clinical achievements in non-CNS diseases validate their efficacy, interdisciplinary collaboration is essential to advance nanoparticles (NPs) engineering, immune evasion, and non-invasive delivery for CNS applications. NPs are indispensable for advancing RNA therapies in brain cancer, with lipid nanoparticles (LNPs) and viral vectors leading clinical translation. Innovations in targeting (e.g., GLUT1, RVG peptide, ApoE mimetic peptide) and non-invasive delivery (e.g., focused ultrasound) are critical to overcome the BBB limitations. This review highlights the different strategies that can be utilized to deliver RNA-based therapies to the brain and summarizes the recent clinical efforts to deliver the RNA.

Medulloblastoma (MB) is the most common childhood brain tumor arising from the cerebellum. PI3K and BRD4 signaling pathways are known to induce MB cell growth, cancer stem cell (CSC) proliferation, and tumor resistance. Further, the tumor suppressor gene TP53 is found to be inactivated in MB due to overexpression of its negative regulator MDM2. In this study, we synthesized MDP5, a potent BRD4/PI3K dual inhibitor, and JW475A, a potent dual MDM2 and XIAP inhibitor. The combination of these two drugs significantly decreased the colony formation capacity compared to individual drugs. Given the challenge of inefficient drug transport across the blood-brain barrier (BBB), we prepared rabies virus glycoprotein (RVG) peptide decorated lipid nanoparticles (LNPs), which showed 4.9 ± 0.1 and 4.8 ± 0.1 % loading for MDP5 and JW475A, respectively. In vivo studies in mice showed that Cy5.5 labeled RVG-LNPs were detected in the brain after systemic administration. Combination drug-loaded RVG-LNPs significantly decreased the MB growth in orthotopic mouse model of MB compared to free drug combination and non-targeted LNPs. This study indicates that MDP5 and JW475A -loaded RVG-LNPs are a promising drug brain delivery system worth exploring further in clinical settings for MB therapy.

Oncogenic KRAS G12D mutations drive pancreatic ductal adenocarcinoma (PDAC) but face therapeutic resistance from pathway reactivation. We synthesized MDP5, a dual BRD4/PI3K inhibitor, to address this issue. When combined with the KRAS G12D inhibitor MRTX1133, MDP5 resensitized resistant cancer cells. This combination synergistically enhanced apoptosis and proliferation inhibition, outperforming the standard-of-care, Gemcitabine (GEM). This dual-inhibition strategy effectively counters resistance mechanisms in KRAS-mutant PDAC, offering a promising therapeutic approach. We formulated MUC4-targeted polymeric nanoparticles co-loading MRTX1133 (8.3%) and MDP5 (7.4%) that exhibited pH-responsive release and uniform morphology. This targeted delivery translated to superior anti-tumor efficacy, as the combination of NPs markedly reduced tumor burden more effectively than single-drug treatments or a polymer-Gemcitabine conjugate. Importantly, this potent therapeutic effect was achieved without inducing detectable liver highlighting the potential, safe, and effective cancer therapy. Mechanistically, dual targeting reduced p-AKT and YAP1, depleted CD44+/ALDH+ cancer-stem-like cells, and reprogrammed the tumor immune microenvironment by elevating CD8a and CD86 while lowering Ly-6G. Targeted co-delivery of MRTX1133 and MDP5 simultaneously inhibits the KRAS G12D and PI3K pathways. This dual-action approach aims to overcome therapeutic resistance, offering potentially more durable and precise treatment for patients with KRAS G12D-mutant pancreatic cancer. STATEMENT OF SIGNIFICANCE Pancreatic ductal adenocarcinoma (PDAC) is commonly driven by KRAS G12D, yet the KRAS G12D inhibitor MRTX1133 faces rapid adaptive resistance and delivery hurdles. We engineered MUC4-targeted polymer nanoparticles that co-deliver MRTX1133 with MDP5, a dual BRD4/PI3K blocker. The particles show uniform size, high loading, and pH-triggered release, increasing intratumoral drug levels versus free drugs. In orthotopic PDAC, the combination outperformed monotherapies and gemcitabine without overt toxicity. Mechanistically, dual inhibition suppresses AKT/YAP signaling, depletes CD44+/ALDH+ cells, and shifts the tumor immune milieu (↑CD8a, ↑CD86, ↓Ly-6G). By integrating molecular targeting with multi-pathway blockade, this work addresses two major barriers—resistance and delivery—and outlines a generalizable strategy to improve precision nano therapy for KRAS-mutant pancreatic cancer.

Medulloblastoma (MB) is a malignant brain tumor that often arises in the cerebellum and has a propensity for spreading to the spinal cord or other parts of the central nervous system (CNS). Craniospinal irradiation (CSI) has long been a cornerstone in the treatment of MB, especially for patients with high-risk or metastatic disease. However, CSI often leads to long-term neurocognitive deficits, including learning disabilities, and growth abnormalities, especially in children. In this study, we aimed to decrease the dose of irradiation and the proliferation of MB by using Volasertib (VSB), a Polo-like kinase 1 (PLK1) specific inhibitor. VSB was highly potent in-vitro with an IC50 of 27.43 nM and 13 nM in HDMB03 and DAOY cells, respectively. However, in the orthotopic MB mouse model, VSB as a free drug did not improve overall survival or decrease tumor burden. Hence, we encapsulated VSB in COG133-conjugated lipid nanoparticles (COG133-LNPs) to circumvent the blood-brain barrier (BBB). We observed that COG-133-LNPs loaded with VSB increased the biodistribution of VSB by three folds than the non-targeted LNPs in the brain. Furthermore, COG133-LNPs along with irradiation decreased tumor burden significantly as compared to VSB or radiation alone. To our observation, COG133-LNPs display high potency in killing MB cells and sensitizing them toward radiation therapy.

Gene therapy has a pivotal role in treating new diseases. In addition to the recent mRNA-based COVID-19 vaccines produced by Pfizer-BioNTech and Moderna against severe acute respiratory syndrome corona virus 2, several new gene therapies have recently been approved as effective treatments for fatal genetic disorders such as Duchenne’s muscular dystrophy, familial transthyretin amyloidosis, hemophilia A, hemophilia B, spinal muscle atrophy, early cerebral autoleukodystrophy, and β-thalassemia. This review provides novel insights into RNA therapeutics focusing on endogenous RNA species, RNA structure and function, and chemical modifications that improve the stability and distribution of RNAs. Furthermore, it includes updated knowledge on clinically approved gene therapies rendering a comprehensive understanding of the biochemical basis and clinical application of gene therapies. Significance Statement There have recently been significant advances in clinical translation of RNA therapeutics. This review discusses the diverse types of RNA species, RNA structure and function, backbone and chemical modifications to RNAs, and every RNA therapeutic approved for clinical use at the time of writing.

Acute myeloid leukemia (AML) remains a highly heterogeneous and aggressive hematologic malignancy with a poor prognosis. Although significant advancements have been made in chemotherapeutic regimens, targeted therapies (e.g., FLT3 and BCL2 inhibitors), and immunotherapies such as antibody-drug conjugates and CAR-T cells, treatment outcomes remain unsatisfactory, due to chemoresistance, off-target toxicities, disease relapse, and limited bioavailability. To address these limitations, nanomedicine and drug delivery systems have emerged as a promising approach to enhance therapeutic efficacy and minimizing adverse effects. This review provides a comprehensive overview of current AML treatments, highlighting both achievements and persistent limitations, with a particular focus on gene therapies under investigation. We then delve into various nanocarrier platforms, mainly lipid-based and polymer-based nanoparticles (NPs), examining their potential to overcome existing clinical challenges in AML therapy by improving drug stability, bioavailability, and leukemic cell targeting. Recent innovations in targeted formulations, such as antibody-, peptide-, and nanobody-conjugated drug delivery systems, have been designed to improve AML specificity. Finally, we discuss the key challenges and future directions in AML treatment, emphasizing the need for continued research in biomaterial innovation, formulation optimization, and precision-targeted approaches to enhance patient outcomes.

We recently demonstrated the therapeutic efficacy of a novel phosphodiesterase 4B (PDE4B) inhibitor, KVA-D88, loaded in mPEG-b-P(CB-co-LA) polymeric nanoparticles (NPs) for alcohol-associated liver disease (AALD) treatment. In this study, we investigated the pharmacokinetics (PK) parameters and biodistribution at whole body and organ (liver) levels of this nanoformulation compared to the KVA-D88 free drug as well as their in vivo efficacies. Following administration, KVA-D88 was distributed to all major organs, with the highest accumulation in the liver and kidney and the lowest accumulation in the brain when loaded into NPs, as quantified using LC-MS/MS after a single intravenous injection in a mouse model with AALD induced by Lieber-DeCarli. Compared to the free drug, KVA-D88-loaded NPs demonstrated significantly higher area under the curve (AUC), maximum plasma concentration (Cmax), and mean residence time (MRT), while the clearance (CI) and volume of distribution (Vss) were significantly lower: 6581.07 vs 3987.24 ng/mL × h (AUC), 4503.13 vs 2947.08 ng/mL (Cmax),1.81 vs 1.57 h (MRT), 725.01 vs 1253.45 mL/h/kg (CI), and 1372.81 vs 1963.01 mL/kg (Vss). In addition, the hepatic drug concentration and proportion of the initial dose of KVA-D88 loaded NPs were reduced in the AALD mice compared to those in healthy mice. Though NP treatment exhibited superior efficacy compared to the free drug, we did not observe a significant difference between the nontargeting NPs and hepatocytes or Kupffer cell-targeting NPs. Our study proved that mPEG-b-P(CB-co-LA) polymeric NPs effectively improved the PK and biodistribution profiles of KVA-D88, highlighting the potential of this nanoformulation as an effective treatment strategy for AALD.

Approximately 90% of pancreatic cancer (PC) contain KRAS mutations. Mutated KRAS activates the downstream oncogenic PI3K/AKT and MEK signaling pathways and induces drug resistance. However, targeting both pathways with different drugs can also lead to excessive toxicity. ONC201 is a dual PI3K/AKT and MEK pathway inhibitor with an excellent safety profile that targets death receptor 5 (DR5) to induce apoptosis. Gemcitabine (GEM) is a first-line chemotherapy in PC, but it is metabolically unstable and can be stabilized by a prodrug approach. In this study, phospho-Akt, phospho-mTOR, and phospho-ERK protein expressions were evaluated in patient PDAC-tissues (n = 10). We used lipid-gemcitabine (L_GEM) conjugate, which is more stable and enters the cells by passive diffusion. Further, we evaluated the efficacy of L_GEM and ONC201 in PC cells and “KrasLSL-G12D; p53LoxP; Pdx1-CreER (KPC) triple mutant xenograft tumor-bearing mice. PDAC patient tissues showed significantly higher levels of p-AKT (Ser473), p-ERK (T202/T204), and p-mTOR compared to surrounding non-cancerous tissues. ONC201 in combination with L_GEM, showed a superior inhibitory effect on the growth of MIA PaCa-2 cells. In our in-vivo study, we found that ONC201 and L_GEM combination prevented neoplastic proliferation via AKT/ERK blockade to overcome chemoresistance and increased T-cell tumor surveillance. Simultaneous inhibition of the PI3K/AKT and MEK pathways with ONC201 is an attractive approach to potentiate the effect of GEM. Our findings provide insight into rational-directed precision chemo and immunotherapy therapy in PDAC.

Liver disease is a significant health burden globally and accounts for 4% of total deaths annually. Alcoholic liver disease (ALD) and metabolism-associated fatty liver disease (MAFLD) are the leading causes of cirrhosis. Extensive studies have investigated the pathogenesis and molecular mechanisms underlying the diseases. However, there remains an urgent need for effective therapeutics. Cyclic adenosine monophosphate (cAMP) is the most studied intracellular second messenger, and its level is directly regulated by phosphodiesterase 4 (PDE4). PDE4 inhibitors are developed and marketed as a large category of drugs. Recent studies have revealed the significant role of cAMP in liver disease progression and evaluated the therapeutic efficacy of PDE4 inhibitors. PDE4 inhibitors exhibited efficacy in ameliorating ALD by reducing inflammation and mediating lipid metabolism. MAFLD, which shares similar disease features to ALD, was attenuated by PDE4 inhibitors due to improved homeostasis of fatty acid metabolism and insulin resistance. Fibrosis, which indicates the late stage of ALD and MAFLD progression, has been shown to improve with PDE4 inhibitors by inhibiting hepatic stellate cell (HSC) activation. However, the results from clinical trials evaluating PDE4 inhibitors for MAFLD management have been conflicting, highlighting the need for further validation and translation of preclinical findings to clinical settings.

Alcohol-associated liver disease (ALD) is a substantial cause of morbidity and mortality worldwide and represents a spectrum of liver injury beginning with hepatic steatosis (fatty liver) progressing to inflammation and culminating in cirrhosis. Multiple factors contribute to ALD progression and disease severity. Here, we overview several crucial mechanisms related to ALD end-stage outcome development, such as epigenetic changes, cell death, hemolysis, hepatic stellate cells activation, and hepatic fatty acid binding protein 4. Additionally, in this review, we also present two clinically relevant models using human precision-cut liver slices and hepatic organoids to examine ALD pathogenesis and progression.

Background and Aims: Chronic liver disease leads to ~2 million deaths annually. Cyclic AMP (cAMP) signaling has long been studied in liver injury, particularly in the regulation of fatty acid (FA) β-oxidation and pro-inflammatory polarization of tissue-resident lymphocytes. Phosphodiesterase 4B inhibition has been explored as a therapeutic modality, but these drugs have had limited success and are known to cause significant adverse effects. The PDE4 inhibitor 2-(4-([2-(5-Chlorothiophen-2-yl)-5-ethyl-6-methylpyrimidin-4-yl]amino)phenyl)acetic acid) (known as A-33) has yet to be explored for the treatment of metabolic diseases. Approach and Results: Herein, we evaluated the efficacy of A-33 in the treatment of animal models of alcohol-associated liver disease and steatotic liver disease. We demonstrated that A-33 effectively ameliorated the signs and symptoms of chronic liver disease, resulting in significant decreases in serum alanine aminotransferase and aspartate aminotransferase levels, decreased overall fat and collagen deposition in the liver, decreased intrahepatic triglyceride concentrations, and normalized expression of genes related to β-oxidation of fatty acids, inflammation, and extracellular matrix deposition. We also designed and synthesized a novel analog of A-33, termed MDL3, which inhibited both phosphodiesterase 4B and PDE5A and was more effective in ameliorating pathophysiological signs and symptoms of liver injury and inflammation. In addition, MDL3 re-sensitized obese mice to glucose and significantly inhibited the pathological remodeling of adipose tissue, which was not observed with A-33 administration. Conclusions: In conclusion, we synthesized and demonstrated that MDL3, a novel phosphodiesterase 4B and PDE5A inhibitor, presents a promising avenue of exploration for treating chronic liver disease.