Pub Date : 2025-12-30DOI: 10.1016/j.jconrel.2025.114591
Guangyu Rong , Yuhan Li , Fang Zhu , Yiteng Lu , Zhengwang Sun , Jiaxu Hong , Yiyun Cheng
Proteolysis-targeting chimeras (PROTACs) offer a powerful strategy for degrading disease-causing proteins. Simultaneous degradation of two oncogenic proteins by PROTACs can yield synergistic therapeutic effects. Here, we developed a dual-targeting fluorous peptide-based PROTAC (DFP-PROTAC) that leverages supramolecular self-assembly for cancer therapy. By conjugating PD-L1- and Bcl-xL-binding peptides to fluorous tags, we generated carrier-free nanoparticles that enter cells via macropinocytosis and achieve efficient endosomal escape, mediating simultaneous degradation of both extracellular PD-L1 and cytosolic Bcl-xL through the ubiquitin-proteasome system. Our results demonstrate that DFP-PROTAC coordinately restores antitumor immunity and apoptotic sensitivity while achieving superior antitumor efficacy with excellent biocompatibility in B16-F10 melanoma-bearing mice, highlighting its therapeutic potential for cancer treatment. This modular fluorous platform offers a versatile strategy for degrading multiple protein targets in the treatment of various diseases.
{"title":"Dual-targeting fluorous peptide proteolysis-targeting chimeras for cancer therapy","authors":"Guangyu Rong , Yuhan Li , Fang Zhu , Yiteng Lu , Zhengwang Sun , Jiaxu Hong , Yiyun Cheng","doi":"10.1016/j.jconrel.2025.114591","DOIUrl":"10.1016/j.jconrel.2025.114591","url":null,"abstract":"<div><div>Proteolysis-targeting chimeras (PROTACs) offer a powerful strategy for degrading disease-causing proteins. Simultaneous degradation of two oncogenic proteins by PROTACs can yield synergistic therapeutic effects. Here, we developed a dual-targeting fluorous peptide-based PROTAC (DFP-PROTAC) that leverages supramolecular self-assembly for cancer therapy. By conjugating PD-L1- and Bcl-xL-binding peptides to fluorous tags, we generated carrier-free nanoparticles that enter cells via macropinocytosis and achieve efficient endosomal escape, mediating simultaneous degradation of both extracellular PD-L1 and cytosolic Bcl-xL through the ubiquitin-proteasome system. Our results demonstrate that DFP-PROTAC coordinately restores antitumor immunity and apoptotic sensitivity while achieving superior antitumor efficacy with excellent biocompatibility in B16-F10 melanoma-bearing mice, highlighting its therapeutic potential for cancer treatment. This modular fluorous platform offers a versatile strategy for degrading multiple protein targets in the treatment of various diseases.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"391 ","pages":"Article 114591"},"PeriodicalIF":11.5,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-30DOI: 10.1016/j.jconrel.2025.114589
Xiaodong Hu , Yujiong Chen , Jian Huang , Shuhang Dong , Kuishuai Xu , Jiadong Cai , Tao Li , Tianrui Wang , Yingze Zhang
Implant-associated infections (IAIs), particularly those involving methicillin-resistant Staphylococcus aureus (MRSA), present a major clinical challenge due to bacterial biofilm formation and localized immunosuppression. To address this, we developed an intelligent bacterial-capture nanodrug, termed Se-MPDA-Cu-D nanoparticles (NPs), designed to enhance immunotherapy through a synergistic antibacterial strategy. This nanoplatform features surface-modified D-alanine for targeted binding to bacterial peptidoglycan, enabling precise localization at infection sites. Within the acidic, glutathione-rich biofilm microenvironment, the nanodrug responsively releases copper ions (Cu2+) and selenium (Se) NPs, triggering a potent chemodynamic therapy that disrupts redox homeostasis and induces a cuproptosis-like death in bacteria. This process is characterized by copper accumulation, lipid peroxidation, DNA damage, and impairment of iron‑sulfur cluster proteins. Beyond its direct antibacterial efficacy, the treatment promotes a robust immunogenic bacterial death (IBD) response, activating dendritic cells, enhancing T-cell infiltration, and reversing the immunosuppressive microenvironment. Furthermore, the released bioactive ions significantly promoted osteogenic differentiation and angiogenesis in vitro. In a rat model of MRSA-infected IAIs, Se-MPDA-Cu-D NPs effectively eradicated biofilms, facilitated substantial new bone regeneration, and restored osseointegration. This multifunctional nanotherapeutic approach presents a promising strategy for combating resistant implant infections by integrating targeted bacterial capture, cuproptosis-like death, and IBD.
{"title":"An intelligent bacterial capture nanodrug enhances immunotherapy for implant-associated infections by inducing cuproptosis-like death in bacteria","authors":"Xiaodong Hu , Yujiong Chen , Jian Huang , Shuhang Dong , Kuishuai Xu , Jiadong Cai , Tao Li , Tianrui Wang , Yingze Zhang","doi":"10.1016/j.jconrel.2025.114589","DOIUrl":"10.1016/j.jconrel.2025.114589","url":null,"abstract":"<div><div>Implant-associated infections (IAIs), particularly those involving methicillin-resistant <em>Staphylococcus aureus</em> (MRSA), present a major clinical challenge due to bacterial biofilm formation and localized immunosuppression. To address this, we developed an intelligent bacterial-capture nanodrug, termed Se-MPDA-Cu-D nanoparticles (NPs), designed to enhance immunotherapy through a synergistic antibacterial strategy. This nanoplatform features surface-modified D-alanine for targeted binding to bacterial peptidoglycan, enabling precise localization at infection sites. Within the acidic, glutathione-rich biofilm microenvironment, the nanodrug responsively releases copper ions (Cu<sup>2+</sup>) and selenium (Se) NPs, triggering a potent chemodynamic therapy that disrupts redox homeostasis and induces a cuproptosis-like death in bacteria. This process is characterized by copper accumulation, lipid peroxidation, DNA damage, and impairment of iron‑sulfur cluster proteins. Beyond its direct antibacterial efficacy, the treatment promotes a robust immunogenic bacterial death (IBD) response, activating dendritic cells, enhancing T-cell infiltration, and reversing the immunosuppressive microenvironment. Furthermore, the released bioactive ions significantly promoted osteogenic differentiation and angiogenesis in vitro. In a rat model of MRSA-infected IAIs, Se-MPDA-Cu-D NPs effectively eradicated biofilms, facilitated substantial new bone regeneration, and restored osseointegration. This multifunctional nanotherapeutic approach presents a promising strategy for combating resistant implant infections by integrating targeted bacterial capture, cuproptosis-like death, and IBD.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114589"},"PeriodicalIF":11.5,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145880802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-30DOI: 10.1016/j.jconrel.2025.114588
Isra Rana , Zhengzheng Zhang , Somy Yoon , Kai Han , James J. Moon , Sejin Son , Jutaek Nam
Cyclic dinucleotides (CDNs) are promising molecular adjuvants targeting stimulator of interferon genes (STING); however, their application has remained limited due to poor in vivo performance. Metal coordination polymer nanoparticles (MCP NPs) formulation with STING-stimulating metal ions can enhance the in vivo pharmacological properties and synergistically amplify STING activation of CDNs. Nevertheless, the controlled fabrication of robust MCP NPs remains challenging. Here, we report a facile nanoengineering of cyclic diadenosine monophosphate (CDA)‑manganese (Mn) coordination complex using a biodegradable mesoporous silica nanoparticle (bMSN) framework. bMSNs efficiently incorporated the nanoscale CDA-Mn complex through simple mixing and reaction, yielding stable CDA-Mn@bMSNs with physicochemical properties programmed by tailor-made bMSNs. CDA-Mn@bMSNs markedly enhanced STING signaling and subsequent activation of dendritic cells, accompanied by improved cellular uptake and cytosolic delivery. Additionally, CDA-Mn@bMSNs generated reactive oxygen species and killed cancer cells by inducing immunogenic cell death and apoptosis. In vivo studies demonstrated potent therapeutic efficacy of CDA-Mn@bMSNs against large established orthotopic melanoma in mice. Local and systemic immune analyses revealed the orchestration of antitumor immunity that supported strong therapeutic outcomes. Moreover, the combination with immune checkpoint blockade therapy further highlighted its potential to improve clinical cancer immunotherapy against highly aggressive and advanced metastatic melanoma. Overall, this study presents a promising engineering strategy for CDN-based MCP NPs to enhance the formulation and performance of STING-targeted cancer metallo-immunotherapy.
{"title":"Nanoengineering of cyclic dinucleotide‑manganese complexes using biodegradable mesoporous silica nanoparticles for cancer metallo-immunotherapy","authors":"Isra Rana , Zhengzheng Zhang , Somy Yoon , Kai Han , James J. Moon , Sejin Son , Jutaek Nam","doi":"10.1016/j.jconrel.2025.114588","DOIUrl":"10.1016/j.jconrel.2025.114588","url":null,"abstract":"<div><div>Cyclic dinucleotides (CDNs) are promising molecular adjuvants targeting stimulator of interferon genes (STING); however, their application has remained limited due to poor <em>in vivo</em> performance. Metal coordination polymer nanoparticles (MCP NPs) formulation with STING-stimulating metal ions can enhance the <em>in vivo</em> pharmacological properties and synergistically amplify STING activation of CDNs. Nevertheless, the controlled fabrication of robust MCP NPs remains challenging. Here, we report a facile nanoengineering of cyclic diadenosine monophosphate (CDA)‑manganese (Mn) coordination complex using a biodegradable mesoporous silica nanoparticle (bMSN) framework. bMSNs efficiently incorporated the nanoscale CDA-Mn complex through simple mixing and reaction, yielding stable CDA-Mn@bMSNs with physicochemical properties programmed by tailor-made bMSNs. CDA-Mn@bMSNs markedly enhanced STING signaling and subsequent activation of dendritic cells, accompanied by improved cellular uptake and cytosolic delivery. Additionally, CDA-Mn@bMSNs generated reactive oxygen species and killed cancer cells by inducing immunogenic cell death and apoptosis. <em>In vivo</em> studies demonstrated potent therapeutic efficacy of CDA-Mn@bMSNs against large established orthotopic melanoma in mice. Local and systemic immune analyses revealed the orchestration of antitumor immunity that supported strong therapeutic outcomes. Moreover, the combination with immune checkpoint blockade therapy further highlighted its potential to improve clinical cancer immunotherapy against highly aggressive and advanced metastatic melanoma. Overall, this study presents a promising engineering strategy for CDN-based MCP NPs to enhance the formulation and performance of STING-targeted cancer metallo-immunotherapy.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114588"},"PeriodicalIF":11.5,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-30DOI: 10.1016/j.jconrel.2025.114583
Patrick Rehorst, Alexander Kros
Logic-gated targeted therapies represent an emerging strategy to enhance specificity in cancer treatment by integrating multiple biological inputs to control therapeutic activation. Inspired by digital logic operations, these systems apply AND, OR and NOT functions to biomolecular processes to restrict activity to defined combinations of tumor-associated cues such as antigen co-expression, acidity or oxidative stress. This review develops a generalized logic-gating framework that unifies the terminology, design principles and mechanistic features of logic-gated systems across two major therapeutic modalities: CAR-T cells, which implement protein-based logic, and nanocarriers, which encode logic chemically. By formalizing concepts such as logic architecture, molecular implementation, mechanistic stage and input signal classification, this framework provides a cross-platform vocabulary for describing, comparing and designing logic-gated therapies. Applying this generalized model reveals characteristic differences in logic behavior across modalities. Protein-based CAR-antigen interactions often yield sharp, digital-like activation thresholds, whereas chemically responsive nanocarriers typically exhibit graded, analog-like release profiles. These behavioral patterns arise from fundamental differences in input signal types, molecular implementations and amplification mechanisms. Overall, this work positions molecular logic gating and multimarker targeting within a unified conceptual structure, clarifies current limitations and variability across platforms, and outlines opportunities for designing next-generation programmable cancer therapies with improved specificity and reduced on-target, off-tumor toxicity.
{"title":"A general logic-gating framework for CAR-T and nanocarrier cancer therapies.","authors":"Patrick Rehorst, Alexander Kros","doi":"10.1016/j.jconrel.2025.114583","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.114583","url":null,"abstract":"<p><p>Logic-gated targeted therapies represent an emerging strategy to enhance specificity in cancer treatment by integrating multiple biological inputs to control therapeutic activation. Inspired by digital logic operations, these systems apply AND, OR and NOT functions to biomolecular processes to restrict activity to defined combinations of tumor-associated cues such as antigen co-expression, acidity or oxidative stress. This review develops a generalized logic-gating framework that unifies the terminology, design principles and mechanistic features of logic-gated systems across two major therapeutic modalities: CAR-T cells, which implement protein-based logic, and nanocarriers, which encode logic chemically. By formalizing concepts such as logic architecture, molecular implementation, mechanistic stage and input signal classification, this framework provides a cross-platform vocabulary for describing, comparing and designing logic-gated therapies. Applying this generalized model reveals characteristic differences in logic behavior across modalities. Protein-based CAR-antigen interactions often yield sharp, digital-like activation thresholds, whereas chemically responsive nanocarriers typically exhibit graded, analog-like release profiles. These behavioral patterns arise from fundamental differences in input signal types, molecular implementations and amplification mechanisms. Overall, this work positions molecular logic gating and multimarker targeting within a unified conceptual structure, clarifies current limitations and variability across platforms, and outlines opportunities for designing next-generation programmable cancer therapies with improved specificity and reduced on-target, off-tumor toxicity.</p>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":" ","pages":"114583"},"PeriodicalIF":11.5,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-30DOI: 10.1016/j.jconrel.2025.114587
Yanjun Liu , Dongqi Sun , Wenshi Li , Zhixiao Zhang , Ce Li , Xiaofang Che , Shenwu Zhang
Immunotherapy has emerged as a transformative approach in cancer treatment. However, its efficacy remains limited in many cases. A key factor contributing to this limitation is metabolic reprogramming within the tumor microenvironment (TME), which suppresses immune cell function and promotes tumor progression. Recently, nanotechnology-based approaches have opened new ways to modulate tumor metabolism and enhance immunotherapy. This review outlines nanoscale strategies aimed at reprogramming tumor metabolism to potentiate antitumor immunity. We begin by discussing the rational design of immune-metabolic nanoregulators, along with key immunometabolic pathways and their regulatory mechanisms. Next, nanotechnology strategies for targeted metabolic intervention at the cellular and microbial levels, as well as the metabolic characteristics of TME are systematically summarized. Furthermore, we highlight recent advances in nanomedicine-based metabolic regulators and evaluate their potential for clinical translation, addressing both opportunities and challenges.
{"title":"Nanomedicine-mediated modulation of tumor metabolism for enhanced immunotherapy","authors":"Yanjun Liu , Dongqi Sun , Wenshi Li , Zhixiao Zhang , Ce Li , Xiaofang Che , Shenwu Zhang","doi":"10.1016/j.jconrel.2025.114587","DOIUrl":"10.1016/j.jconrel.2025.114587","url":null,"abstract":"<div><div>Immunotherapy has emerged as a transformative approach in cancer treatment. However, its efficacy remains limited in many cases. A key factor contributing to this limitation is metabolic reprogramming within the tumor microenvironment (TME), which suppresses immune cell function and promotes tumor progression. Recently, nanotechnology-based approaches have opened new ways to modulate tumor metabolism and enhance immunotherapy. This review outlines nanoscale strategies aimed at reprogramming tumor metabolism to potentiate antitumor immunity. We begin by discussing the rational design of immune-metabolic nanoregulators, along with key immunometabolic pathways and their regulatory mechanisms. Next, nanotechnology strategies for targeted metabolic intervention at the cellular and microbial levels, as well as the metabolic characteristics of TME are systematically summarized. Furthermore, we highlight recent advances in nanomedicine-based metabolic regulators and evaluate their potential for clinical translation, addressing both opportunities and challenges.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114587"},"PeriodicalIF":11.5,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145880800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-29DOI: 10.1016/j.jconrel.2025.114584
Geng Li , Mohammad Massumi , Hajar Owji , Ge Yang , Eugenia Girda , Arash Hatefi
The objective of this research was to develop a targeted clinically translatable stem cell-based system for the treatment of drug-resistant and metastatic ovarian cancer. To achieve this goal, we genetically engineered and isolated an adipose-derived stem cell (ASC) clone that expresses secretory human carboxylesterase-2 (shCE2) enzyme extracellularly and yeast cytosine deaminase: uracil phosphoribosyl transferase (yCD:UPRT) enzyme intracellularly for targeted combination enzyme/prodrug therapy. The shCE2 enzyme converts the prodrug irinotecan into its potent active metabolite SN-38, while yCD:UPRT transforms the prodrug 5-FC into the cytotoxic agent 5-FU. To evaluate the therapeutic potential of this system, we utilized ovarian cancer cells derived from patients with drug-resistant recurrent disease. All four lines exhibited sensitivity to SN-38 at sub-nanomolar concentrations, with a direct correlation observed between SN-38 sensitivity and expression levels of topoisomerase I. The cancer cells were subsequently xenografted into mice to establish metastatic intraperitoneal tumors. Following confirmation of active migration of the engineered ASCs toward the tumor sites through real-time bioluminescent imaging and immunohistochemistry, mice were treated either with prodrugs alone or in combination with the engineered ASCs. Therapeutic response and tumor relapses were assessed using quantitative bioluminescent imaging. The results of this study demonstrated that mice receiving the combination of ASCs and prodrugs exhibited complete eradication of metastatic tumors with no clinically significant toxicity to normal tissues. Overall, this study demonstrates that the developed ASC-directed dual enzyme/prodrug system is a highly effective and targeted approach for treating refractory ovarian tumors, with significant potential for clinical translation.
{"title":"Engineered tumor-tropic mesenchymal stem cells as targeted therapeutic delivery systems for refractory Ovarian cancer","authors":"Geng Li , Mohammad Massumi , Hajar Owji , Ge Yang , Eugenia Girda , Arash Hatefi","doi":"10.1016/j.jconrel.2025.114584","DOIUrl":"10.1016/j.jconrel.2025.114584","url":null,"abstract":"<div><div>The objective of this research was to develop a targeted clinically translatable stem cell-based system for the treatment of drug-resistant and metastatic ovarian cancer. To achieve this goal, we genetically engineered and isolated an adipose-derived stem cell (ASC) clone that expresses secretory human carboxylesterase-2 (shCE2) enzyme extracellularly and yeast cytosine deaminase: uracil phosphoribosyl transferase (yCD:UPRT) enzyme intracellularly for targeted combination enzyme/prodrug therapy. The shCE2 enzyme converts the prodrug irinotecan into its potent active metabolite SN-38, while yCD:UPRT transforms the prodrug 5-FC into the cytotoxic agent 5-FU. To evaluate the therapeutic potential of this system, we utilized ovarian cancer cells derived from patients with drug-resistant recurrent disease. All four lines exhibited sensitivity to SN-38 at sub-nanomolar concentrations, with a direct correlation observed between SN-38 sensitivity and expression levels of topoisomerase I. The cancer cells were subsequently xenografted into mice to establish metastatic intraperitoneal tumors. Following confirmation of active migration of the engineered ASCs toward the tumor sites through real-time bioluminescent imaging and immunohistochemistry, mice were treated either with prodrugs alone or in combination with the engineered ASCs. Therapeutic response and tumor relapses were assessed using quantitative bioluminescent imaging. The results of this study demonstrated that mice receiving the combination of ASCs and prodrugs exhibited complete eradication of metastatic tumors with no clinically significant toxicity to normal tissues. Overall, this study demonstrates that the developed ASC-directed dual enzyme/prodrug system is a highly effective and targeted approach for treating refractory ovarian tumors, with significant potential for clinical translation.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114584"},"PeriodicalIF":11.5,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-29DOI: 10.1016/j.jconrel.2025.114581
Xue Zhan , Hang Xiao , Qian Wang , Juan Luo , Li Ma , Xuelian Zhang , Jianyuan Tang , Xiangrui Meng
The therapeutic efficacy of natural killer (NK) cell–based immunotherapies remains constrained by insufficient recruitment, suboptimal activation, and limited persistence of NK cells within the immunosuppressive tumor microenvironment. A multifunctional NK cell nano-engager (FBS) is developed to enhance NK cell recruitment, activation, and proliferation at the tumor site. This nanoplatform facilitates the tumor-responsive release of ferrous ions (Fe2+) and brusatol (Bru), thereby amplifying the Fenton reaction and promoting the accumulation of reactive oxygen species (ROS). The resulting oxidative stress induces both ferroptosis and immunogenic cell death (ICD), disrupts the tumor's antioxidant defenses, and stimulates the release of damage-associated molecular patterns (DAMPs), enhancing antigen presentation and eliciting multi-stage immune activation. FBS–Bru markedly enhances the intratumoral NK cell infiltration and activation, remodels the local immune microenvironment, and initiates pro-inflammatory signaling that reinforces NK cell cytotoxicity and persistence. This nanotherapeutic construct demonstrates significant potential as an NK cell nano-engager, serving as an alternative to immune checkpoint inhibition. This strategy offers a targeted and multi-modal approach to potentiate innate immunity, improve tumor-specific cytolytic efficacy, and ensure biosafety.
{"title":"Natural killer cell nano-engagers drive ferroptosis–immunomodulation synergy via inhibition of the Interleukin-6-JAK2-STAT3 Axis","authors":"Xue Zhan , Hang Xiao , Qian Wang , Juan Luo , Li Ma , Xuelian Zhang , Jianyuan Tang , Xiangrui Meng","doi":"10.1016/j.jconrel.2025.114581","DOIUrl":"10.1016/j.jconrel.2025.114581","url":null,"abstract":"<div><div>The therapeutic efficacy of natural killer (NK) cell–based immunotherapies remains constrained by insufficient recruitment, suboptimal activation, and limited persistence of NK cells within the immunosuppressive tumor microenvironment. A multifunctional NK cell nano-engager (FBS) is developed to enhance NK cell recruitment, activation, and proliferation at the tumor site. This nanoplatform facilitates the tumor-responsive release of ferrous ions (Fe<sup>2+</sup>) and brusatol (Bru), thereby amplifying the Fenton reaction and promoting the accumulation of reactive oxygen species (ROS). The resulting oxidative stress induces both ferroptosis and immunogenic cell death (ICD), disrupts the tumor's antioxidant defenses, and stimulates the release of damage-associated molecular patterns (DAMPs), enhancing antigen presentation and eliciting multi-stage immune activation. FBS–Bru markedly enhances the intratumoral NK cell infiltration and activation, remodels the local immune microenvironment, and initiates pro-inflammatory signaling that reinforces NK cell cytotoxicity and persistence. This nanotherapeutic construct demonstrates significant potential as an NK cell nano-engager, serving as an alternative to immune checkpoint inhibition. This strategy offers a targeted and multi-modal approach to potentiate innate immunity, improve tumor-specific cytolytic efficacy, and ensure biosafety.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114581"},"PeriodicalIF":11.5,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-29DOI: 10.1016/j.jconrel.2025.114582
Naveena Konduru , Caiji Wang , Siyu Liu , Gaorong Zhang , Liting Zheng , Zeqi Zhao , Xuanyi Li , Wen Jiang , Huiying Zhang , Shen Ding , Preethi Priyanka Musunuru , Jingbin Hao , Xi Shi , Yuehua Qiao
Drug delivery to the inner ear remains a major hurdle to effective therapy, underscoring the importance of precision-based delivery strategies. Diabetes-induced hearing loss (DHL) is a debilitating condition with limited therapeutic options, primarily driven by oxidative stress and microvascular damage in the cochlea. Current treatments are ineffective, highlighting the paramount need for novel strategies. Gelatin methacryloyl (GelMA) hydrogels, owing to their biocompatibility and tunable physicochemical properties, enables in situ crosslinking using ultraviolet (UV) light for precise localization of therapeutic agents. Berberine, renowned for its antioxidant and anti-inflammatory efficacy, has shown potential in mitigating diabetes-related complications and certain types of hearing loss. However, its limited solubility and poor permeability across the blood-labyrinth barrier (BLB) hinder its systemic efficacy. To circumvent this, we designed a localized, injectable, and photo-crosslinked GelMA conjugated berberine chloride hydrate (BCH) hydrogel for sustained cochlear drug delivery. Our results demonstrated that GelMA-BCH hydrogel exhibited excellent biocompatibility, robust adhesion, and prolonged cochlear drug retention, enhancing therapeutic outcomes. Liquid chromatography-mass spectrometry (LC-MS) confirmed higher perilymph BCH concentration following localized GelMA-BCH hydrogel administration compared to systemic free BCH delivery. In streptozotocin (STZ)-induced diabetic mice, GelMA-BCH hydrogel treatment demonstrated significant recovery in auditory function, with improved auditory brainstem responses (ABR) thresholds compared to untreated diabetic controls. Morphological analysis revealed preserved cochlear integrity, particularly through protection of outer hair cells (OHCs) and cochlear synapses. In vitro, GelMA-BCH protected auditory House Ear Institute-Organ of Corti 1 (HEI-OC1) cells by reducing STZ-induced oxidative stress, thereby suppressing inflammatory cytokines and mitochondrial-mediated apoptosis, leading to markedly improved cellular resilience. These findings reinforce the potential application of GelMA-BCH hydrogel as a targeted, bioactive therapeutic strategy for cochlear protection in DHL, offering a novel strategy for future clinical translation and address the urgent unmet need in otology and regenerative medicine.
{"title":"Local cochlear delivery of berberine chloride hydrate via an injectable photo-crosslinked hydrogel for treating diabetes- induced hearing loss","authors":"Naveena Konduru , Caiji Wang , Siyu Liu , Gaorong Zhang , Liting Zheng , Zeqi Zhao , Xuanyi Li , Wen Jiang , Huiying Zhang , Shen Ding , Preethi Priyanka Musunuru , Jingbin Hao , Xi Shi , Yuehua Qiao","doi":"10.1016/j.jconrel.2025.114582","DOIUrl":"10.1016/j.jconrel.2025.114582","url":null,"abstract":"<div><div>Drug delivery to the inner ear remains a major hurdle to effective therapy, underscoring the importance of precision-based delivery strategies. Diabetes-induced hearing loss (DHL) is a debilitating condition with limited therapeutic options, primarily driven by oxidative stress and microvascular damage in the cochlea. Current treatments are ineffective, highlighting the paramount need for novel strategies. Gelatin methacryloyl (GelMA) hydrogels, owing to their biocompatibility and tunable physicochemical properties, enables in situ crosslinking using ultraviolet (UV) light for precise localization of therapeutic agents. Berberine, renowned for its antioxidant and anti-inflammatory efficacy, has shown potential in mitigating diabetes-related complications and certain types of hearing loss. However, its limited solubility and poor permeability across the blood-labyrinth barrier (BLB) hinder its systemic efficacy. To circumvent this, we designed a localized, injectable, and photo-crosslinked GelMA conjugated berberine chloride hydrate (BCH) hydrogel for sustained cochlear drug delivery. Our results demonstrated that GelMA-BCH hydrogel exhibited excellent biocompatibility, robust adhesion, and prolonged cochlear drug retention, enhancing therapeutic outcomes. Liquid chromatography-mass spectrometry (LC-MS) confirmed higher perilymph BCH concentration following localized GelMA-BCH hydrogel administration compared to systemic free BCH delivery. In streptozotocin (STZ)-induced diabetic mice, GelMA-BCH hydrogel treatment demonstrated significant recovery in auditory function, with improved auditory brainstem responses (ABR) thresholds compared to untreated diabetic controls. Morphological analysis revealed preserved cochlear integrity, particularly through protection of outer hair cells (OHCs) and cochlear synapses. In vitro, GelMA-BCH protected auditory House Ear Institute-Organ of Corti 1 (HEI-OC1) cells by reducing STZ-induced oxidative stress, thereby suppressing inflammatory cytokines and mitochondrial-mediated apoptosis, leading to markedly improved cellular resilience. These findings reinforce the potential application of GelMA-BCH hydrogel as a targeted, bioactive therapeutic strategy for cochlear protection in DHL, offering a novel strategy for future clinical translation and address the urgent unmet need in otology and regenerative medicine.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114582"},"PeriodicalIF":11.5,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-29DOI: 10.1016/j.jconrel.2025.114586
Shan He , Pei-Juan Wu , Li Zhang , Jia-Xue Wu , Hou-Li Li , Kun Yi , Qiu-Yun Sun , Zi-Yang Wang , Yu-Xin Yue , Dong-Sheng Guo , Ke Hu , Xiao-Bei Huang , Wen-Juan Wan
Myopia is one of the most common visual impairments worldwide. Recent studies suggest that scleral hypoxia may act as an early trigger for myopia, initiating oxidative stress (OS) that disrupts extracellular matrix (ECM) remodeling and, in turn, drives axial elongation. In this study, we constructed a novel hypoxia-responsive host-guest complex, DOX@SAC4A, by encapsulating doxycycline (DOX) within sulfonated azocalix[4]arene (SAC4A). In vitro, this system significantly reduced DOX cytotoxicity and enabled efficient hypoxia-triggered drug release. Moreover, the intrinsic activity of SAC4A synergistically enhanced the antioxidant and anti-apoptotic effects of DOX, helping to maintain ECM homeostasis. In vivo studies further confirmed that DOX@SAC4A selectively targeted hypoxic sclera and markedly increased local drug accumulation. Consequently, it effectively suppressed myopia progression in guinea pigs by delaying axial elongation and alleviating myopic refractive shift. In conclusion, DOX@SAC4A is a multifunctional drug delivery system that offers both therapeutic effects and targeted delivery, with promising potential for myopia prevention and control.
{"title":"Hypoxia-responsive Azocalixarene-doxycycline host-guest complex for synergistic myopia control","authors":"Shan He , Pei-Juan Wu , Li Zhang , Jia-Xue Wu , Hou-Li Li , Kun Yi , Qiu-Yun Sun , Zi-Yang Wang , Yu-Xin Yue , Dong-Sheng Guo , Ke Hu , Xiao-Bei Huang , Wen-Juan Wan","doi":"10.1016/j.jconrel.2025.114586","DOIUrl":"10.1016/j.jconrel.2025.114586","url":null,"abstract":"<div><div>Myopia is one of the most common visual impairments worldwide. Recent studies suggest that scleral hypoxia may act as an early trigger for myopia, initiating oxidative stress (OS) that disrupts extracellular matrix (ECM) remodeling and, in turn, drives axial elongation. In this study, we constructed a novel hypoxia-responsive host-guest complex, DOX@SAC4A, by encapsulating doxycycline (DOX) within sulfonated azocalix[4]arene (SAC4A). In vitro, this system significantly reduced DOX cytotoxicity and enabled efficient hypoxia-triggered drug release. Moreover, the intrinsic activity of SAC4A synergistically enhanced the antioxidant and anti-apoptotic effects of DOX, helping to maintain ECM homeostasis. In vivo studies further confirmed that DOX@SAC4A selectively targeted hypoxic sclera and markedly increased local drug accumulation. Consequently, it effectively suppressed myopia progression in guinea pigs by delaying axial elongation and alleviating myopic refractive shift. In conclusion, DOX@SAC4A is a multifunctional drug delivery system that offers both therapeutic effects and targeted delivery, with promising potential for myopia prevention and control.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114586"},"PeriodicalIF":11.5,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-26DOI: 10.1016/j.jconrel.2025.114560
Ling Mei, Jingdong Rao, Yayuan Liu, Man Li, Zhirong Zhang, Qin He
{"title":"Corrigendum to “Effective treatment of the primary tumor and lymph node metastasis by polymeric micelles with variable particle sizes” [Journal of Controlled Release, Volume 292 (2018), 67–77]","authors":"Ling Mei, Jingdong Rao, Yayuan Liu, Man Li, Zhirong Zhang, Qin He","doi":"10.1016/j.jconrel.2025.114560","DOIUrl":"10.1016/j.jconrel.2025.114560","url":null,"abstract":"","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"390 ","pages":"Article 114560"},"PeriodicalIF":11.5,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145837466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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