Pub Date : 2026-03-09Epub Date: 2026-02-20DOI: 10.1021/acs.biomac.5c02780
Xinyu Zhang , Mingda Zhao , Jiadong Li , Zhulian Li , Lei Tong , Hailong Wang , Gongbing Liu , Chunyu Tan , Yujiang Fan , Yong Sun
Oxidative stress disrupts the synthesis–degradation balance of the extracellular matrix in osteoarthritic (OA) cartilage, resulting in the loss of type II collagen (COLII). Here, we developed self-assembled nanoparticles (PE@NPs) driven by hydrophobic interaction, π–π stacking interactions and hydrogen bonding, forming an epigallocatechin-3-gallate (EGCG) core and a polyethylene glycol (PEG) shell. Compared with free EGCG, which possesses potent but short-lived antioxidant activity, PE@NPs improved molecular stability, extending reactive oxygen species scavenging activity to 24 h. Furthermore, PE@NPs significantly suppressed interleukin-1 β-induced COLII degradation in OA chondrocytes. Transcriptomic analysis revealed that PE@NPs upregulated genes involved in antioxidant defense (Selenop), cartilage homeostasis (Cytl1 and DKK3) and subchondral bone remodeling (Omd). In vivo, PE@NPs exhibited a more significant therapeutic effect than free EGCG, notably attenuating COLII degradation and improving subchondral bone mass, thereby delaying OA progression. Overall, these findings identify PE@NPs as a safe and effective therapeutic approach for OA.
{"title":"Self-Assembled EGCG Nanoparticles Achieved Long-Term ROS Scavenging to Delay Osteoarthritis Progression","authors":"Xinyu Zhang , Mingda Zhao , Jiadong Li , Zhulian Li , Lei Tong , Hailong Wang , Gongbing Liu , Chunyu Tan , Yujiang Fan , Yong Sun","doi":"10.1021/acs.biomac.5c02780","DOIUrl":"10.1021/acs.biomac.5c02780","url":null,"abstract":"<div><div>Oxidative stress disrupts the synthesis–degradation balance of the extracellular matrix in osteoarthritic (OA) cartilage, resulting in the loss of type II collagen (COLII). Here, we developed self-assembled nanoparticles (PE@NPs) driven by hydrophobic interaction, π–π stacking interactions and hydrogen bonding, forming an epigallocatechin-3-gallate (EGCG) core and a polyethylene glycol (PEG) shell. Compared with free EGCG, which possesses potent but short-lived antioxidant activity, PE@NPs improved molecular stability, extending reactive oxygen species scavenging activity to 24 h. Furthermore, PE@NPs significantly suppressed interleukin-1 β-induced COLII degradation in OA chondrocytes. Transcriptomic analysis revealed that PE@NPs upregulated genes involved in antioxidant defense (<em>Selenop</em>), cartilage homeostasis (<em>Cytl1</em> and <em>DKK3</em>) and subchondral bone remodeling (<em>Omd</em>). In vivo, PE@NPs exhibited a more significant therapeutic effect than free EGCG, notably attenuating COLII degradation and improving subchondral bone mass, thereby delaying OA progression. Overall, these findings identify PE@NPs as a safe and effective therapeutic approach for OA.</div></div><div><div><span><figure><span><img><ol><li><span><span>Download: <span>Download high-res image (169KB)</span></span></span></li><li><span><span>Download: <span>Download full-size image</span></span></span></li></ol></span></figure></span></div></div>","PeriodicalId":30,"journal":{"name":"Biomacromolecules","volume":"27 3","pages":"Pages 2319-2330"},"PeriodicalIF":5.4,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146256666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-09Epub Date: 2026-02-05DOI: 10.1021/acs.biomac.5c02569
Haolong Ma , Qingdeng Fan , Yanwei Zeng , Haobin Cai , Chunmei Chen , Ya Huang , Bin Ren , Zongheng Li , Lin Huang , Zheyu Shen , Jing Yang
The persistence of cancer stem cells (CSCs) within deep tumors is a primary driver of therapeutic failure and relapse. Most large nanoparticles fail to penetrate deep tumors, and extra-small nanoparticles suffer from poor retention in tumors. To solve the “penetration-retention paradox”, herein, we developed special extra-small iron oxide nanoparticles (IO) featuring an “AND logic-gate”-driven self-assembly to achieve both deep penetration and long retention in large tumors for efficient CSCs dismission. Typically, the poly(ethylene glycol) (PEG) shield of IO is functionalized with a tyrosine (T) and thioketal (TK) linker followed by β-lapachone (LAP) loading, forming TIO-TK-PEG@LAP. (i) The extra-small TIO-TK-PEG@LAP can penetrate into deep tumors, whose H2O2 cleaves the TK linker, detaching the PEG shield and exposing T residues. (ii) The H+ facilitates the release of Fe2+ from IO to react with H2O2, generating hydroxyl radicals (•OH). (iii) The •OH catalyzes covalent cross-linking of T residues, driving in situ self-assembly into IO aggregates (∼100 nm), prolonging tumor retention. (iv) After cellular uptake, the IO aggregates are degraded in the endosomes, releasing LAP and Fe2+. (v) LAP can be catalyzed to generate substantial H2O2, which synergizes with Fe2+ to amplify the Fenton reaction, generating explosive •OH to trigger ferroptosis of tumor cells.
{"title":"AND-Gate-Enabled Extra-Small Nanoparticles Achieve Deep Penetration and Long Retention in Large Tumors for Efficient Cancer Stem Cells Dismission","authors":"Haolong Ma , Qingdeng Fan , Yanwei Zeng , Haobin Cai , Chunmei Chen , Ya Huang , Bin Ren , Zongheng Li , Lin Huang , Zheyu Shen , Jing Yang","doi":"10.1021/acs.biomac.5c02569","DOIUrl":"10.1021/acs.biomac.5c02569","url":null,"abstract":"<div><div>The persistence of cancer stem cells (CSCs) within deep tumors is a primary driver of therapeutic failure and relapse. Most large nanoparticles fail to penetrate deep tumors, and extra-small nanoparticles suffer from poor retention in tumors. To solve the “penetration-retention paradox”, herein, we developed special extra-small iron oxide nanoparticles (IO) featuring an “AND logic-gate”-driven self-assembly to achieve both deep penetration and long retention in large tumors for efficient CSCs dismission. Typically, the poly(ethylene glycol) (PEG) shield of IO is functionalized with a tyrosine (T) and thioketal (TK) linker followed by β-lapachone (LAP) loading, forming TIO-TK-PEG@LAP. (i) The extra-small TIO-TK-PEG@LAP can penetrate into deep tumors, whose H<sub>2</sub>O<sub>2</sub> cleaves the TK linker, detaching the PEG shield and exposing T residues. (ii) The H<sup>+</sup> facilitates the release of Fe<sup>2+</sup> from IO to react with H<sub>2</sub>O<sub>2</sub>, generating hydroxyl radicals (<sup>•</sup>OH). (iii) The <sup>•</sup>OH catalyzes covalent cross-linking of T residues, driving <em>in situ</em> self-assembly into IO aggregates (∼100 nm), prolonging tumor retention. (iv) After cellular uptake, the IO aggregates are degraded in the endosomes, releasing LAP and Fe<sup>2+</sup>. (v) LAP can be catalyzed to generate substantial H<sub>2</sub>O<sub>2</sub>, which synergizes with Fe<sup>2+</sup> to amplify the Fenton reaction, generating explosive <sup>•</sup>OH to trigger ferroptosis of tumor cells.</div></div><div><div><span><figure><span><img><ol><li><span><span>Download: <span>Download high-res image (247KB)</span></span></span></li><li><span><span>Download: <span>Download full-size image</span></span></span></li></ol></span></figure></span></div></div>","PeriodicalId":30,"journal":{"name":"Biomacromolecules","volume":"27 3","pages":"Pages 2234-2250"},"PeriodicalIF":5.4,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-09Epub Date: 2026-02-10DOI: 10.1021/acs.biomac.5c01659
Deepika Sharma , Soumen K. Dubey , Poonam K. Sharma , Nishima Wangoo , Rohit K. Sharma
The diphenylalanine (FF) and its derivatives are widely studied for their self-assembly, mechanical strength, and diverse applications in materials and the biomedicine field. To develop a stable, and synthetically accessible nonpeptidic FF mimic, 14 aromatic derivatives of l-phenylalanine (A1 to A7) and l-phenylglycine (G1 to G7) were designed and synthesized to investigate the structure–property relationships. The systematic variation of aromatic groups, electronic substitution, and C-terminal protection enabled control of the intermolecular interactions. The morphological study revealed that rigid derivatives formed rod-like structures through strong π–π stacking, whereas the flexible derivatives produced fibrillar morphologies. The C-terminal modification promoted plate-like assemblies, while the electronic effects led to microplate formation. Here, the N-terminal phenylacetyl protection enhances the molecular flexibility of derivative A2, enabling it to mimic the morphological and optical behavior of FF-dipeptide while offering enhanced stability and highlighting a robust nonpeptidic platform for bioinspired nanomaterials.
{"title":"Unravelling Non-Peptidic Analogues as Phe–Phe Mimetics: Insights into Synthesis, Self-Assembly, Structural Analysis, and Optical Properties","authors":"Deepika Sharma , Soumen K. Dubey , Poonam K. Sharma , Nishima Wangoo , Rohit K. Sharma","doi":"10.1021/acs.biomac.5c01659","DOIUrl":"10.1021/acs.biomac.5c01659","url":null,"abstract":"<div><div>The diphenylalanine (FF) and its derivatives are widely studied for their self-assembly, mechanical strength, and diverse applications in materials and the biomedicine field. To develop a stable, and synthetically accessible nonpeptidic FF mimic, 14 aromatic derivatives of <span>l</span>-phenylalanine (A1 to A7) and <span>l</span>-phenylglycine (G1 to G7) were designed and synthesized to investigate the structure–property relationships. The systematic variation of aromatic groups, electronic substitution, and C-terminal protection enabled control of the intermolecular interactions. The morphological study revealed that rigid derivatives formed rod-like structures through strong π–π stacking, whereas the flexible derivatives produced fibrillar morphologies. The C-terminal modification promoted plate-like assemblies, while the electronic effects led to microplate formation. Here, the N-terminal phenylacetyl protection enhances the molecular flexibility of derivative A2, enabling it to mimic the morphological and optical behavior of FF-dipeptide while offering enhanced stability and highlighting a robust nonpeptidic platform for bioinspired nanomaterials.</div></div><div><div><span><figure><span><img><ol><li><span><span>Download: <span>Download high-res image (209KB)</span></span></span></li><li><span><span>Download: <span>Download full-size image</span></span></span></li></ol></span></figure></span></div></div>","PeriodicalId":30,"journal":{"name":"Biomacromolecules","volume":"27 3","pages":"Pages 1831-1845"},"PeriodicalIF":5.4,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146148445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-09Epub Date: 2026-02-12DOI: 10.1021/acs.biomac.5c01662
Prajakatta B. Mulay , D. Christopher Radford , Brayan Rondon , Bruna Favetta , Benjamin S. Schuster , Jia Niu , Adam J. Gormley
Cationic polymers present an attractive platform for gene delivery. However, these highly charged macromolecules can also lead to cytotoxicity. Therefore, there is a strong unmet need to develop efficacious polymeric gene delivery vehicles with high biocompatibility. Here, we leverage recent advances in polymer chemistry to develop backbone-degradable cationic copolymers and evaluate their potential as gene delivery vehicles. Specifically, polycations were prepared via copolymerization with macrocyclic allylic sulfides, which can participate in PET-RAFT polymerization via radical ring-opening cascade copolymerization to install degradable backbone segments. A polymer library with varying degradabilities was prepared and evaluated using a model GFP plasmid to transfect U-2 OS cells. Incorporation of degradable groups into the copolymer backbone improved transfection efficiency 10-fold at low amine/phosphate (N/P) ratios without increasing cytotoxicity, thereby enhancing their value as gene delivery carriers. We hypothesize that degradability may enhance the complex’s disassembly kinetics in the cytosol, enabling more efficient payload release.
{"title":"Gene Delivery Mediated by Backbone-Degradable RAFT Copolymers","authors":"Prajakatta B. Mulay , D. Christopher Radford , Brayan Rondon , Bruna Favetta , Benjamin S. Schuster , Jia Niu , Adam J. Gormley","doi":"10.1021/acs.biomac.5c01662","DOIUrl":"10.1021/acs.biomac.5c01662","url":null,"abstract":"<div><div>Cationic polymers present an attractive platform for gene delivery. However, these highly charged macromolecules can also lead to cytotoxicity. Therefore, there is a strong unmet need to develop efficacious polymeric gene delivery vehicles with high biocompatibility. Here, we leverage recent advances in polymer chemistry to develop backbone-degradable cationic copolymers and evaluate their potential as gene delivery vehicles. Specifically, polycations were prepared via copolymerization with macrocyclic allylic sulfides, which can participate in PET-RAFT polymerization via radical ring-opening cascade copolymerization to install degradable backbone segments. A polymer library with varying degradabilities was prepared and evaluated using a model GFP plasmid to transfect U-2 OS cells. Incorporation of degradable groups into the copolymer backbone improved transfection efficiency 10-fold at low amine/phosphate (N/P) ratios without increasing cytotoxicity, thereby enhancing their value as gene delivery carriers. We hypothesize that degradability may enhance the complex’s disassembly kinetics in the cytosol, enabling more efficient payload release.</div></div><div><div><span><figure><span><img><ol><li><span><span>Download: <span>Download high-res image (81KB)</span></span></span></li><li><span><span>Download: <span>Download full-size image</span></span></span></li></ol></span></figure></span></div></div>","PeriodicalId":30,"journal":{"name":"Biomacromolecules","volume":"27 3","pages":"Pages 1846-1856"},"PeriodicalIF":5.4,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146163016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-09Epub Date: 2026-02-13DOI: 10.1021/acs.biomac.5c02707
Sheng Jin , Jin Zhou , Xinfeng Tao , Yunkai Lu , Mengying Xiao , Wenbin Liu , Shaoliang Lin
Alternating azopolymers are notable in smart material design for their unique self-assembly behavior, which stems from the precisely controlled hydrophilic–hydrophobic balance and stimuli-responsiveness. Herein, we report the facile synthesis of light- and pH-responsive alternating copolymers, namely P(Azo-alt-PyEG2tBu), via Ugi multicomponent polymerization using commercially available azobenzene and pyridine derivatives. P(Azo-alt-PyEG2tBu) specifically self-assembled into polymersomes with ultrathin membranes (∼2.0 nm) through a folded chain model, serving as potential fluorescent probes when end groups are dye-modified. These polymersomes exhibit reversible morphological transitions between vesicles and micelles under alternating UV and blue light irradiation, driven by the azobenzene isomerization. Similarly, acidic pH triggers disassembly of the polymersomes due to protonation of pyridine groups. Light- and pH-triggered cargo-release studies reveal efficient encapsulation and controlled release of hydrophilic cargos. We have established a versatile strategy for constructing dual-responsive nanocarriers with tailored morphologies and stimuli-adaptive functionalities, advancing smart material applications in drug delivery and bioimaging.
{"title":"Facile Synthesis of Alternating Azopolymers via Ugi Multicomponent Polymerization toward Photo- and pH-Responsive Polymersomes","authors":"Sheng Jin , Jin Zhou , Xinfeng Tao , Yunkai Lu , Mengying Xiao , Wenbin Liu , Shaoliang Lin","doi":"10.1021/acs.biomac.5c02707","DOIUrl":"10.1021/acs.biomac.5c02707","url":null,"abstract":"<div><div>Alternating azopolymers are notable in smart material design for their unique self-assembly behavior, which stems from the precisely controlled hydrophilic–hydrophobic balance and stimuli-responsiveness. Herein, we report the facile synthesis of light- and pH-responsive alternating copolymers, namely P(Azo-<em>alt</em>-PyEG<sub>2</sub> <em>t</em>Bu), via Ugi multicomponent polymerization using commercially available azobenzene and pyridine derivatives. P(Azo-<em>alt</em>-PyEG<sub>2</sub> <em>t</em>Bu) specifically self-assembled into polymersomes with ultrathin membranes (∼2.0 nm) through a folded chain model, serving as potential fluorescent probes when end groups are dye-modified. These polymersomes exhibit reversible morphological transitions between vesicles and micelles under alternating UV and blue light irradiation, driven by the azobenzene isomerization. Similarly, acidic pH triggers disassembly of the polymersomes due to protonation of pyridine groups. Light- and pH-triggered cargo-release studies reveal efficient encapsulation and controlled release of hydrophilic cargos. We have established a versatile strategy for constructing dual-responsive nanocarriers with tailored morphologies and stimuli-adaptive functionalities, advancing smart material applications in drug delivery and bioimaging.</div></div><div><div><span><figure><span><img><ol><li><span><span>Download: <span>Download high-res image (108KB)</span></span></span></li><li><span><span>Download: <span>Download full-size image</span></span></span></li></ol></span></figure></span></div></div>","PeriodicalId":30,"journal":{"name":"Biomacromolecules","volume":"27 3","pages":"Pages 2297-2308"},"PeriodicalIF":5.4,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-09Epub Date: 2026-02-23DOI: 10.1021/acs.biomac.5c02014
Meixin Wang , Shi Yang , Yifei Xu , Jianwei Wang , Yage Zhang , Qingming Ma , Chuanliang Feng , Yang Song
Tumor-targeting intracellular chemotherapy represents a precision therapy to overcome multidrug resistance (MDR) in ovarian cancers, yet efficient drug enrichment in resistant cells is difficult. Peptide-based coacervates have emerged as an intracellular reservoir for drug delivery; however, enhancing their antitumor efficacy requires precise control over the spatiotemporal distribution of drugs within tumor cells. To address this, we developed a nucleus-localizing coacervate system by complexing a cell-penetrating peptide with sodium alginate (SA), which enables efficient delivery of the DNA-binding drug doxorubicin (DOX) into the cell nucleus. Remarkably, the fluorescence partition coefficient of DOX in the nucleus of ovarian cancer cells increased by 4 ± 0.5-fold compared to coacervate-free controls, while nuclear drug retention was extended from approximately 4 to 36 h. This nucleus-localized drug delivery and sustained retention enhanced the killing efficacy of DNA-targeting medicine against MDR cells by 60 ± 5% at clinical doses, offering a promising therapeutic strategy for treating drug-resistant ovarian cancers. Keywords: complexed coacervates, intracellular drug delivery, ovarian cancer, multi-drug resistance, cell-penetrating peptide
{"title":"Nucleus-Localizing Coacervates Synergize with Chemotherapy for the Treatment of Drug-Resistant Ovarian Tumors","authors":"Meixin Wang , Shi Yang , Yifei Xu , Jianwei Wang , Yage Zhang , Qingming Ma , Chuanliang Feng , Yang Song","doi":"10.1021/acs.biomac.5c02014","DOIUrl":"10.1021/acs.biomac.5c02014","url":null,"abstract":"<div><div>Tumor-targeting intracellular chemotherapy represents a precision therapy to overcome multidrug resistance (MDR) in ovarian cancers, yet efficient drug enrichment in resistant cells is difficult. Peptide-based coacervates have emerged as an intracellular reservoir for drug delivery; however, enhancing their antitumor efficacy requires precise control over the spatiotemporal distribution of drugs within tumor cells. To address this, we developed a nucleus-localizing coacervate system by complexing a cell-penetrating peptide with sodium alginate (SA), which enables efficient delivery of the DNA-binding drug doxorubicin (DOX) into the cell nucleus. Remarkably, the fluorescence partition coefficient of DOX in the nucleus of ovarian cancer cells increased by 4 ± 0.5-fold compared to coacervate-free controls, while nuclear drug retention was extended from approximately 4 to 36 h. This nucleus-localized drug delivery and sustained retention enhanced the killing efficacy of DNA-targeting medicine against MDR cells by 60 ± 5% at clinical doses, offering a promising therapeutic strategy for treating drug-resistant ovarian cancers. Keywords: complexed coacervates, intracellular drug delivery, ovarian cancer, multi-drug resistance, cell-penetrating peptide</div></div><div><div><span><figure><span><img><ol><li><span><span>Download: <span>Download high-res image (147KB)</span></span></span></li><li><span><span>Download: <span>Download full-size image</span></span></span></li></ol></span></figure></span></div></div>","PeriodicalId":30,"journal":{"name":"Biomacromolecules","volume":"27 3","pages":"Pages 1915-1926"},"PeriodicalIF":5.4,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147269271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-09Epub Date: 2026-02-02DOI: 10.1021/acs.biomac.5c01993
Harpreet Kaur , Devansh Swadia , Ishani Sharma , S. M. Rose , Sharmistha Sinha
Mutations in the tumor suppressor p53, particularly the R273 mutation, are major drivers of poor prognosis and treatment resistance in colorectal cancer (CRC). Additionally, reports have recently shown that environmental factors and metabolites within the tumor microenvironment act together to drive and compound tumor progression. This study investigates the interactions between secondary bile acids, lithocholic acid (LCA), and deoxycholic acid (DCA), and mutant p53 in CRC. We show that while the secondary bile acids have a minimal effect on wild-type p53, it significantly promotes the aggregation of the R273H and R273C mutant variants, an effect that is markedly enhanced in the presence of the chemotherapy drug doxorubicin in cell lines. Our biophysical studies demonstrate that the DNA binding is compromised in mutant p53 and is completely lost in the presence of the bile acids and doxorubicin. Further, we show that LCA binds to mutant p53 with high affinity, inducing the formation of large oligomeric assemblies and biomolecular condensates. Binding studies reveal stronger interactions between the bile acids and mutant p53, resulting in increased aggregation, as confirmed by imaging studies. Additionally, bile acids induce biomolecular condensate formation in mutant p53, sequestering doxorubicin within these structures and suggesting a mechanism for chemoresistance. These findings highlight the role of bile acids in promoting mutant p53 aggregation and therapy resistance, suggesting potential new therapeutic targets for p53 mutant CRC.
{"title":"Bile Acid-Induced Aggregation and Phase Separation of Mutant p53 Leads to Doxorubicin Sequestration","authors":"Harpreet Kaur , Devansh Swadia , Ishani Sharma , S. M. Rose , Sharmistha Sinha","doi":"10.1021/acs.biomac.5c01993","DOIUrl":"10.1021/acs.biomac.5c01993","url":null,"abstract":"<div><div>Mutations in the tumor suppressor p53, particularly the R273 mutation, are major drivers of poor prognosis and treatment resistance in colorectal cancer (CRC). Additionally, reports have recently shown that environmental factors and metabolites within the tumor microenvironment act together to drive and compound tumor progression. This study investigates the interactions between secondary bile acids, lithocholic acid (LCA), and deoxycholic acid (DCA), and mutant p53 in CRC. We show that while the secondary bile acids have a minimal effect on wild-type p53, it significantly promotes the aggregation of the R273H and R273C mutant variants, an effect that is markedly enhanced in the presence of the chemotherapy drug doxorubicin in cell lines. Our biophysical studies demonstrate that the DNA binding is compromised in mutant p53 and is completely lost in the presence of the bile acids and doxorubicin. Further, we show that LCA binds to mutant p53 with high affinity, inducing the formation of large oligomeric assemblies and biomolecular condensates. Binding studies reveal stronger interactions between the bile acids and mutant p53, resulting in increased aggregation, as confirmed by imaging studies. Additionally, bile acids induce biomolecular condensate formation in mutant p53, sequestering doxorubicin within these structures and suggesting a mechanism for chemoresistance. These findings highlight the role of bile acids in promoting mutant p53 aggregation and therapy resistance, suggesting potential new therapeutic targets for p53 mutant CRC.</div></div><div><div><span><figure><span><img><ol><li><span><span>Download: <span>Download high-res image (150KB)</span></span></span></li><li><span><span>Download: <span>Download full-size image</span></span></span></li></ol></span></figure></span></div></div>","PeriodicalId":30,"journal":{"name":"Biomacromolecules","volume":"27 3","pages":"Pages 1891-1904"},"PeriodicalIF":5.4,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146103085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-09Epub Date: 2026-02-13DOI: 10.1021/acs.biomac.5c02634
Valeria Castelletto, Ian W Hamley
A simple dipeptide WR (tryptophan–arginine) in the form of salts with organic acids tartaric acid or crotonic acid is shown to form glasses through a benign preparation route by evaporation of aqueous solution. The glasses have a remarkable range of properties including moldability, high transparency across a broad range of wavelengths, and fluorescence. The glasses show self-healing and adhesive properties, and have accessible glass transition temperatures. The glasses are shown to be amorphous via small-angle and wide-angle X-ray scattering (SAXS/WAXS) and scanning electron microscopy (SEM). Remarkably, the glasses are found to have a chiral structure, as shown by circular dichroism (CD) spectroscopy. Investigation of glass precursor dipeptide salt solutions shows that the glasses form from an initial unordered solution containing chiral peptide molecules. The diverse properties of the dipeptide glass materials points to a wide range of potential future applications.
{"title":"Chiral Glass Formation by Dipeptide Salts","authors":"Valeria Castelletto, Ian W Hamley","doi":"10.1021/acs.biomac.5c02634","DOIUrl":"10.1021/acs.biomac.5c02634","url":null,"abstract":"<div><div>A simple dipeptide WR (tryptophan–arginine) in the form of salts with organic acids tartaric acid or crotonic acid is shown to form glasses through a benign preparation route by evaporation of aqueous solution. The glasses have a remarkable range of properties including moldability, high transparency across a broad range of wavelengths, and fluorescence. The glasses show self-healing and adhesive properties, and have accessible glass transition temperatures. The glasses are shown to be amorphous via small-angle and wide-angle X-ray scattering (SAXS/WAXS) and scanning electron microscopy (SEM). Remarkably, the glasses are found to have a chiral structure, as shown by circular dichroism (CD) spectroscopy. Investigation of glass precursor dipeptide salt solutions shows that the glasses form from an initial unordered solution containing chiral peptide molecules. The diverse properties of the dipeptide glass materials points to a wide range of potential future applications.</div></div><div><div><span><figure><span><img><ol><li><span><span>Download: <span>Download high-res image (93KB)</span></span></span></li><li><span><span>Download: <span>Download full-size image</span></span></span></li></ol></span></figure></span></div></div>","PeriodicalId":30,"journal":{"name":"Biomacromolecules","volume":"27 3","pages":"Pages 2251-2259"},"PeriodicalIF":5.4,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Peptide-protected gold nanoclusters (P-AuNCs) were ideal candidates for constructing antibacterial agents. However, the individual P-AuNCs could only exert limited target behavior and antibacterial efficiency. Herein, CA2R5/GSH-AuNCs were synthesized using CA2R5 and glutathione (GSH), and their purification was efficiently performed by adjusting pH from 7.0 to 9.0. DNA aptamer targeting Staphylococcus aureus was used to assemble CA2R5/GSH-AuNCs to form Apt-CA2R5/GSH-AuNCs. After purification at pH 9.0, Apt-CA2R5/GSH-AuNCs were mixed with silver ions to form Apt-CA2R5/GSH-Ag-AuNCs. The antibacterial activity of Apt-CA2R5/GSH-Ag-AuNCs was much higher than that of CA2R5/GSH-Ag-AuNCs formed by mixing CA2R5/GSH-AuNCs with silver ions. The inhibitory concentration of Apt-CA2R5/GSH-Ag-AuNCs against S. aureus did not change after 40 steps of successive bacterial cultivation. The formation of bacterial biofilms was inhibited after treatment with Apt-CA2R5/GSH-Ag-AuNCs. The death of the bacteria was attributed to disruption of the cell membrane and change of normal metabolism. This work could provide a new concept for constructing antibacterial peptide-based nanomaterials.
{"title":"DNA Aptamer-Induced Assemblies of Peptide-Protected Silver–Gold Nanoclusters to Enhance Antibacterial Performance","authors":"Jinliang Ma, Mengmeng Yang, Bing Wang, Mengxuan Zhang, Zitong Wang, Bin Zhang, Mingfu Niu","doi":"10.1021/acs.biomac.5c01209","DOIUrl":"10.1021/acs.biomac.5c01209","url":null,"abstract":"<div><div>Peptide-protected gold nanoclusters (P-AuNCs) were ideal candidates for constructing antibacterial agents. However, the individual P-AuNCs could only exert limited target behavior and antibacterial efficiency. Herein, CA<sub>2</sub>R<sub>5</sub>/GSH-AuNCs were synthesized using CA<sub>2</sub>R<sub>5</sub> and glutathione (GSH), and their purification was efficiently performed by adjusting pH from 7.0 to 9.0. DNA aptamer targeting Staphylococcus aureus was used to assemble CA<sub>2</sub>R<sub>5</sub>/GSH-AuNCs to form Apt-CA<sub>2</sub>R<sub>5</sub>/GSH-AuNCs. After purification at pH 9.0, Apt-CA<sub>2</sub>R<sub>5</sub>/GSH-AuNCs were mixed with silver ions to form Apt-CA<sub>2</sub>R<sub>5</sub>/GSH-Ag-AuNCs. The antibacterial activity of Apt-CA<sub>2</sub>R<sub>5</sub>/GSH-Ag-AuNCs was much higher than that of CA<sub>2</sub>R<sub>5</sub>/GSH-Ag-AuNCs formed by mixing CA<sub>2</sub>R<sub>5</sub>/GSH-AuNCs with silver ions. The inhibitory concentration of Apt-CA<sub>2</sub>R<sub>5</sub>/GSH-Ag-AuNCs against S. aureus did not change after 40 steps of successive bacterial cultivation. The formation of bacterial biofilms was inhibited after treatment with Apt-CA<sub>2</sub>R<sub>5</sub>/GSH-Ag-AuNCs. The death of the bacteria was attributed to disruption of the cell membrane and change of normal metabolism. This work could provide a new concept for constructing antibacterial peptide-based nanomaterials.</div></div><div><div><span><figure><span><img><ol><li><span><span>Download: <span>Download high-res image (191KB)</span></span></span></li><li><span><span>Download: <span>Download full-size image</span></span></span></li></ol></span></figure></span></div></div>","PeriodicalId":30,"journal":{"name":"Biomacromolecules","volume":"27 3","pages":"Pages 1806-1818"},"PeriodicalIF":5.4,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146199690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-09Epub Date: 2026-02-07DOI: 10.1021/acs.biomac.5c01941
Diane Jeong , Junsu Kim , Yunjung Kim, Heejin Jun, Soomin Eom, Sebyung Kang
Targeted therapy enables the selective delivery of therapeutics to specific cells, reducing off-target effects and improving efficacy. HER2-targeted approaches are particularly effective in HER2-positive breast cancer. Here, we engineered protein nanoparticles based on Aquifex aeolicus lumazine synthase (AaLS) to simultaneously display HER2-binding nanobodies (aHER2Nb; A10 or 2Rb17C) and/or TRAIL on their surface. Both single- and dual-ligand AaLS protein nanoparticles retained an intact cage architecture and showed strong binding to HER2-overexpressing breast cancer cells. Although SK-BR3 and MDA-MB-453 cells were resistant to soluble TRAIL, TRAIL-presenting AaLS (AaLS/TRAIL) markedly enhanced cytotoxicity by promoting death receptor clustering. Unexpectedly, dual-ligand AaLS protein nanoparticles (AaLS/TRAIL/A10 and AaLS/TRAIL/2Rb17C) exhibited biphasic cytotoxicity; low doses synergistically enhanced apoptosis in HER2-positive cells, whereas higher doses reduced efficacy, likely due to the activation of survival signaling. These results highlight the importance of dose optimization for maximizing the use of TRAIL-based targeted therapies.
{"title":"HER2-Targeting and TRAIL-Presenting Protein Nanoparticles Induce a Concentration-Dependent Biphasic Response in HER2-Positive Breast Cancer Cells","authors":"Diane Jeong , Junsu Kim , Yunjung Kim, Heejin Jun, Soomin Eom, Sebyung Kang","doi":"10.1021/acs.biomac.5c01941","DOIUrl":"10.1021/acs.biomac.5c01941","url":null,"abstract":"<div><div>Targeted therapy enables the selective delivery of therapeutics to specific cells, reducing off-target effects and improving efficacy. HER2-targeted approaches are particularly effective in HER2-positive breast cancer. Here, we engineered protein nanoparticles based on Aquifex aeolicus lumazine synthase (AaLS) to simultaneously display HER2-binding nanobodies (aHER2Nb; A10 or 2Rb17C) and/or TRAIL on their surface. Both single- and dual-ligand AaLS protein nanoparticles retained an intact cage architecture and showed strong binding to HER2-overexpressing breast cancer cells. Although SK-BR3 and MDA-MB-453 cells were resistant to soluble TRAIL, TRAIL-presenting AaLS (AaLS/TRAIL) markedly enhanced cytotoxicity by promoting death receptor clustering. Unexpectedly, dual-ligand AaLS protein nanoparticles (AaLS/TRAIL/A10 and AaLS/TRAIL/2Rb17C) exhibited biphasic cytotoxicity; low doses synergistically enhanced apoptosis in HER2-positive cells, whereas higher doses reduced efficacy, likely due to the activation of survival signaling. These results highlight the importance of dose optimization for maximizing the use of TRAIL-based targeted therapies.</div></div><div><div><span><figure><span><img><ol><li><span><span>Download: <span>Download high-res image (74KB)</span></span></span></li><li><span><span>Download: <span>Download full-size image</span></span></span></li></ol></span></figure></span></div></div>","PeriodicalId":30,"journal":{"name":"Biomacromolecules","volume":"27 3","pages":"Pages 1878-1890"},"PeriodicalIF":5.4,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146130444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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