-weighted MR imaging of NASH model mice is performed after injecting Mn@BRNPs intravenously. The MR signal enhancement in the liver relative to muscle gradually increases up to 8 weeks of NASH progression, but decreases significantly as NASH progresses to the cirrhosis-like stage at weeks 10 and 12. A new dual input pseudo-three-compartment model is developed to provide information on NASH stage with a single MRI scan. It is also demonstrated that the ROS-responsive Mn@BRNPs can be used to monitor the efficacy of potential anti-NASH drugs with conventional MRI. The findings suggest that the ROS-responsive Mn@BRNPs have the potential to serve as an efficient MRI contrast for monitoring NASH progression and its transition to the cirrhosis-like stage.

Drug Delivery In article number 2311283, Hee-Seung Lee, Sangyong Jon, and co-workers have develop an organ-selective drug delivery platform based on a library of glycocalyx-mimicking nanoparticles (GlyNPs). Direct in vivo library screening enable identification of GlyNP hits targeting liver, spleen, lung, kidneys, heart, and brain and, moreover, each organ-selective GlyNP hit shows cellular tropism within the organ. When liver-, kidney-, and spleen-selective GlyNP hits are equipped with therapeutics, the formulations effectively alleviated symptoms in organ-associated disease models.

Organ-selective drug delivery is expected to maximize the efficacy of various therapeutic modalities while minimizing their systemic toxicity. Lipid nanoparticles and polymersomes can direct the organ-selective delivery of mRNAs or gene editing machineries, but their delivery is limited to mostly liver, spleen, and lung. A platform that enables delivery to these and other target organs is urgently needed. Here, a library of glycocalyx-mimicking nanoparticles (GlyNPs) comprising five randomly combined sugar moieties is generated, and direct in vivo library screening is used to identify GlyNPs with preferential biodistribution in liver, spleen, lung, kidneys, heart, and brain. Each organ-targeting GlyNP hit show cellular tropism within the organ. Liver, kidney, and spleen-targeting GlyNP hits equipped with therapeutics effectively can alleviate the symptoms of acetaminophen-induced liver injury, cisplatin-induced kidney injury, and immune thrombocytopenia in mice, respectively. Furthermore, the differential organ targeting of GlyNP hits is influenced not by the protein corona but by the sugar moieties displayed on their surface. It is envisioned that the GlyNP-based platform may enable the organ- and cell-targeted delivery of therapeutic cargoes.

Cancer-targeting ligands used for nanomedicines have been limited mostly to antibodies, peptides, aptamers, and small molecules thus far. Here, a library of glycocalyx-mimicking nanoparticles as a platform to enable screening and identification of cancer-targeting nanomedicines is reported. Specifically, a library of 31 artificial glycopolymers composed of either homogeneous or heterogeneous display of five different sugar moieties (β-glucose, β-galactose, α-mannose, β-N-acetyl glucosamine, and β-N-acetyl galactosamine) is converted to a library of glyconanoparticles (GlyNPs). GlyNPs optimal for targeting CT26, DU145, A549, and PC3 tumors are systematically screened and identified. The cypate-conjugated GlyNP displaying α-mannose and β-N-acetyl glucosamine show selective targeting and potent photothermal therapeutic efficacy against A549 human lung tumors. The docetaxel-contained GlyNP displaying β-glucose, β-galactose, and α-mannose demonstrate targeted chemotherapy against DU145 human prostate tumors. The results presented herein collectively demonstrate that the GlyNP library is a versatile platform enabling the identification of cancer-targeting glyconanoparticles and suggest its potential applicability for targeting various diseased cells beyond cancer.

Cancer Therapy As glycocalyx-directed binding interactions are prevalent in cancer cells and are used for cell–cell communication and cell adhesion through carbohydrate-mediated interactions, Hee-Seung Lee, Sangyong Jon, and co-workers have developed a nanomedicine platform based on a library of glycocalyx-mimicking nanoparticles that enables screening and identification of cancer-cell-selective glyconanoparticles, as described in article number 2203993. This work demonstrates the potential of the glycocalyx-mimicking nanoparticle platform for use in targeted cancer therapy.

Culture platforms for human induced pluripotent stem cells (hiPSCs) that rely on feeder cells or extracellular matrices (ECMs) face substantial limitations for practical regenerative medicine applications, including undefined components, high costs, and a tendency to maintain hiPSCs in the primed pluripotent state, which has lower differentiation potential than the naïve state. To overcome these challenges, we developed a long-term hiPSC culture platform based on a cross-linked cyclosiloxane polymer matrix that preserves pluripotency with naïve-like characteristics. Through optimization, we identified an ideal cyclosiloxane polymer matrix, designated as poly-Z, which supported the growth of hiPSCs as spheroids. Even after 60 d of continuous culture, hiPSC spheroids maintained on poly-Z retained pluripotency markers and normal karyotypes at levels comparable to those of hiPSC colonies cultured on conventional vitronectin (VN)-coated plates. Furthermore, mRNA sequencing revealed that hiPSC spheroids cultured on poly-Z not only exhibited up-regulation of typical pluripotency-related genes but also showed increased expression of genes associated with the naïve pluripotent state, in contrast to the primed state observed in hiPSCs cultured on VN-coated plates or in suspension culture. Gene ontology (GO) analysis and gene set enrichment analysis (GSEA) further suggested that the down-regulation of genes involved in cell-ECM interactions contributed to the induction of naïve-like features in poly-Z-cultured hiPSC spheroids. These findings highlight the potential of cross-linked cyclosiloxane-based polymer matrices as an innovative platform for human pluripotent stem cell research and regenerative medicine.

Recent studies have highlighted the therapeutic potential of targeting tumor neoantigens in solid tumors; however, its efficacy in breast cancer remains unclear. Here, we evaluate the impact of tumor neoantigen-targeted strategies in a syngeneic mouse mammary carcinoma model. Mice previously exposed to 4T1 tumor cells (PETCs) or treated with tumor cell-derived lysates (TdLs) exhibited robust antitumor immunity, leading to reduced tumor growth and metastasis through tumor immune microenvironment remodeling. TdL administration in mice harboring orthotopic tumors significantly enhanced the efficacy of immune checkpoint blockade, suggesting its potential as an immunotherapeutic adjuvant. To further optimize neoantigen-based approaches, we developed a lipid nanoparticle (LNP)-based delivery system for neoantigen peptides, which effectively suppressed tumor progression and metastasis in vivo. Mechanistically, this strategy promoted antigen-specific T cell activation and reshaped the tumor immune landscape, enhancing immune-mediated tumor rejection. These findings underscore the therapeutic promise of personalized tumor neoantigen-targeted immunotherapy in breast cancer and support its further evaluation in clinical settings.

-weighted MR imaging of NASH model mice is performed after injecting Mn@BRNPs intravenously. The MR signal enhancement in the liver relative to muscle gradually increases up to 8 weeks of NASH progression, but decreases significantly as NASH progresses to the cirrhosis-like stage at weeks 10 and 12. A new dual input pseudo-three-compartment model is developed to provide information on NASH stage with a single MRI scan. It is also demonstrated that the ROS-responsive Mn@BRNPs can be used to monitor the efficacy of potential anti-NASH drugs with conventional MRI. The findings suggest that the ROS-responsive Mn@BRNPs have the potential to serve as an efficient MRI contrast for monitoring NASH progression and its transition to the cirrhosis-like stage.

Drug Delivery In article number 2311283, Hee-Seung Lee, Sangyong Jon, and co-workers have develop an organ-selective drug delivery platform based on a library of glycocalyx-mimicking nanoparticles (GlyNPs). Direct in vivo library screening enable identification of GlyNP hits targeting liver, spleen, lung, kidneys, heart, and brain and, moreover, each organ-selective GlyNP hit shows cellular tropism within the organ. When liver-, kidney-, and spleen-selective GlyNP hits are equipped with therapeutics, the formulations effectively alleviated symptoms in organ-associated disease models.

Organ-selective drug delivery is expected to maximize the efficacy of various therapeutic modalities while minimizing their systemic toxicity. Lipid nanoparticles and polymersomes can direct the organ-selective delivery of mRNAs or gene editing machineries, but their delivery is limited to mostly liver, spleen, and lung. A platform that enables delivery to these and other target organs is urgently needed. Here, a library of glycocalyx-mimicking nanoparticles (GlyNPs) comprising five randomly combined sugar moieties is generated, and direct in vivo library screening is used to identify GlyNPs with preferential biodistribution in liver, spleen, lung, kidneys, heart, and brain. Each organ-targeting GlyNP hit show cellular tropism within the organ. Liver, kidney, and spleen-targeting GlyNP hits equipped with therapeutics effectively can alleviate the symptoms of acetaminophen-induced liver injury, cisplatin-induced kidney injury, and immune thrombocytopenia in mice, respectively. Furthermore, the differential organ targeting of GlyNP hits is influenced not by the protein corona but by the sugar moieties displayed on their surface. It is envisioned that the GlyNP-based platform may enable the organ- and cell-targeted delivery of therapeutic cargoes.

Cancer-targeting ligands used for nanomedicines have been limited mostly to antibodies, peptides, aptamers, and small molecules thus far. Here, a library of glycocalyx-mimicking nanoparticles as a platform to enable screening and identification of cancer-targeting nanomedicines is reported. Specifically, a library of 31 artificial glycopolymers composed of either homogeneous or heterogeneous display of five different sugar moieties (β-glucose, β-galactose, α-mannose, β-N-acetyl glucosamine, and β-N-acetyl galactosamine) is converted to a library of glyconanoparticles (GlyNPs). GlyNPs optimal for targeting CT26, DU145, A549, and PC3 tumors are systematically screened and identified. The cypate-conjugated GlyNP displaying α-mannose and β-N-acetyl glucosamine show selective targeting and potent photothermal therapeutic efficacy against A549 human lung tumors. The docetaxel-contained GlyNP displaying β-glucose, β-galactose, and α-mannose demonstrate targeted chemotherapy against DU145 human prostate tumors. The results presented herein collectively demonstrate that the GlyNP library is a versatile platform enabling the identification of cancer-targeting glyconanoparticles and suggest its potential applicability for targeting various diseased cells beyond cancer.