During the last seventy years, studies on mammalian sperm cells have demonstrated the essential role of capacitation, hyperactivation and the acrosome reaction in the acquisition of fertilization ability. These studies revealed the important biochemical and physiological changes that sperm undergo in their travel throughout the female genital tract, including changes in membrane fluidity, the activation of soluble adenylate cyclase, increases in intracellular pH and Ca2+ and the development of motility. Sperm are highly polarized cells, with a resting membrane potential of about −40 mV, which must rapidly adapt to the ionic changes occurring through the sperm membrane. This review summarizes the current knowledge about the relationship between variations in the sperm potential membrane, including depolarization and hyperpolarization, and their correlation with changes in sperm motility and capacitation to further lead to the acrosome reaction, a calcium-dependent exocytosis process. We also review the functionality of different ion channels that are present in spermatozoa in order to understand their association with human infertility., This research was funded by the Ministry of Science and Innovation, Spain, grant numbers PID2020-119949RB-100 and TED2021-132681B-I00, CPP2021-008458, co-founded by the European Union and by Instituto de Salud Carlos III, co-funded by European Union (ERDF/ESF, “Investing in your future”), grant nember PI20/01131., Peer reviewed

We report for the first time the controlled drug release from a nanoscale Zr-based metal-organic framework (MOF), UiO-66, in the presence of the enzyme alkaline phosphatase (ALP). This unprecedented reactivity was possible thanks to the prior functionalization of the MOF with N-PEG-PO ligands, which were designed for three specific aims: (1) to impart colloidal stability in phosphate-containing media; (2) to endow the MOF with multifunctionality thanks to azide groups for the covalent attachment of an imaging agent by click-chemistry; and (3) to confer stimuli-responsive properties, specifically the selective release of doxorubicin triggered by the enzymatic activity of ALP. Cell studies revealed that the functionalization of the MOF with N-(PEG)-PO ligands improved their intracellular stability and led to a sustained drug release compared to the bare MOF. More importantly, an enhanced drug release was observed in cells with higher expression of ALP genes (HeLa versus MDA-MB-231 and MCF7), confirming the ALP-responsiveness of the system inside living cells., Financial support was provided by Spanish Ministry of Science,
Innovation and Universities and the Spanish Research Agency
(RYC-2019-027527-I to C.C.-C and PID2020-119949RB-I00
to NK), the Andalusian Ministry of Economy, Science and
Innovation cofinanced by the European Regional Development
Fund (ERDF) from FEDER and the European Social Fund
(ESF) (PY20_00882 to NK, and CV20-04221 to NK), the
PAIDI Program from the Andalusian Government (FQM-313
to NK), the Fundación Vencer el Cancer (B.R.G. and V.C),
the Spanish association against the Cancer AECC investigator
grant (INVES20033COMA to V.C.), and the Marie
Skłodowska-Curie Individual Fellowship (MSCA-IF Oncoinflammation
101026137 to V.C. and B.R.G.).

The field of stimuli-responsive supramolecular biomaterials has rapidly advanced in recent years, with potential applications in diverse areas such as cancer theranostics, tissue engineering, and catalysis. However, designing molecular materials that exhibit predetermined hierarchical self-assembly to control the size, morphology, surface chemistry, and responsiveness of the final nanostructures remains a significant challenge. In this study, we present a divergent synthetic approach for the fabrication of spherical micelles and functional 1D-glyconanotube-based photoresponsive gels from structurally related diazobenzene/diacetylene glycolipids. The resulting nanostructures were characterized using NMR, TEM, and SEM, confirming the formation of spherical and tubular nanostructures in both the gel and solution states. Upon UV irradiation, a reversible gel-sol transition was observed, resulting from the photoswitching of the azobenzene unit from the stretched trans form to the compact, metastable cis form. Our gels were shown to enable spatio-temporal control of the adhesion and release of the lectin Concanavalin A, demonstrating potential use as regenerable biomaterials to fight against infections with toxins and pathogens. Additionally, our micelles and gels were evaluated as nanocontainers for loading and controlled release of hydrophobic dyes and antitumoural agents, suggesting their possible use as smart theranostic drug delivery systems., Financial support was provided by the Spanish Ministry of Science and Innovation (Ref: PID2020-119949RB-I00/AEI/10.13039/501100011033), the Andalusian Ministry of Economy, Science and Innovation cofinanced by the European Regional Development Fund (ERDF) from FEDER and the European Social Fund (ESF) (PY20_00882 and CV20-04221), the CSIC (CSIC-COV19-047) the PAIDI Program from the Andalusian Government (FQM-313). The COST action CA-18132 ‘‘Functional Glyconanomaterials for the Development of Diagnostic and Targeted Therapeutic Probe’’ is also acknowledged. ERB, was supported by FPU predoctoral fellowship (FPU15/04267), from Spanish Ministry of Education, Culture and Sports. We also thank the Centre of Research Technology and Innovation of the University of Seville (CITIUS) for the use of TEM, SEM,
FESEM, and NMR facilities, No

Zirconium-based MOFs, such as PCN-222 (MOF-545), have gained attention due to their regular porosity, tuneable pore size, versatile structure and exceptional thermal/chemical stability. However, the synthesis of PCN-222 using traditional batch processes suffers from limitations in productivity, scalability, and control over size and morphology. This study presents a paradigm shift from batch to continuous flow (c.f.) synthesis for the efficient production of PCN-222. The optimization of batch conditions and exploration of c.f. parameters enabled the synthesis of high-quality PCN-222 with Space-Time-Yield (STY) exceeding 950 kg m−3 day−1. The c.f. approach offered advantages including improved resource efficiency, safer chemical handling, and scalability. The integration of ultrasound-assisted technique into the c.f. facilitated the shaping of PCN-222 into prolate ellipsoids, making it suitable for applications in drug delivery and catalysis. The successful substitution of hazardous solvents with greener alternatives further enhanced the sustainability of the process. Finally, the loading of a thio-N-acetylgalactosamine-PEG-sulfate ligand on PCN-222 in tandem c.f., expanded the potentialities of the flow synthetic approach. This study not only advances the field of MOF synthesis but also paves the way for efficient and sustainable manufacturing processes in c.f. synthesis of nanoparticles and functionalized nanoparticles for active drug delivery., Financial support was provided by the Andalusian Ministry of Economy, Science and Innovation in the framework of the Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI 2020, programme 54ª “Investigación científica e innovación”, “POSTDOC_21_00594”), the Spanish Ministry of Science and Innovation (Ref: PID2020-119949RB-I00/AEI/10.13039/501100011033), the Andalusian Ministry of Economy, Science and Innovation cofinanced by the European Regional Development Fund (ERDF) from FEDER and the European Social Fund (ESF) (PY20_00882 and CV20-04221). The COST action CA-18132 “Functional Glyconanomaterials for the Development of Diagnostic and Targeted Therapeutic Probe” is also acknowledged. The authors acknowledge Dr. Carolina Carrillo-Carrión for her technical assistance in the initial batch experiments conducted for this work., No

The functionalization of nanoparticles with specific ligands, such as antibodies, peptides, and small molecules, plays a critical role in achieving targeted delivery, enhancing biocompatibility, and controlling drug release. However, to date, practically no attention has been paid to the design of green ligands. Herein, an innovative approach to develop a sustainable ligand for nanoparticle functionalization is reported. Its synthesis involved a photochemical thio-ene “click” reaction between the natural compounds phosphatidylcoline, the main component of lecithin, and cysteine, followed by a reductive amination with mannose, a sugar of growing interest for biomedical targeting, in a continuous flow hydrogenation reactor. Comprehensive characterization techniques, including nuclear magnetic resonance (NMR), mass spectrometry (MS), Fourier-transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS) and elemental analysis, confirmed the structure and properties of the novel ligand. The environmental sustainability of the ligand was evaluated determining some green metrics using the EATOS software. The obtained E-factor was compared with a conventional PEG-based ligand. The newly developed lecithin-derived ligand was successfully used to functionalize diverse NP platforms, including the MOFs MIL-101(Fe), PCN-222, UiO-66, and iron nanoparticles (in the form of akaganeite), demonstrating its potential in nanomedicine applications., Financial support was provided by the Andalusian Ministry of Economy, Science and Innovation in the framework of the Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI 2020, programme 54ª “Investigación científica e innovación”, “POSTDOC_21_00594”), the Spanish Ministry of Science and Innovation (Ref: PID2020-119949RB-I00), the Andalusian Ministry of Economy, Science and Innovation cofinanced by the European Regional Development Fund (ERDF) from FEDER and the European Social Fund (ESF) (PY20_00882 and CV20-04221). The COST action CA-18132 “Functional Glyconanomaterials for the Development of Diagnostic and Targeted Therapeutic Probe” is also acknowledged. The COST action CA-22147 “European metal–organic framework network: combining research and development to promote technological solutions” (EU4MOFs) is also acknowledged., Peer reviewed

Chemicals and CAS Registry Numbers
Biocompatible Materials
Carbohydrates
Metal-Organic Frameworks, The unique features of metal-organic frameworks (MOFs) such as biodegradability, reduced toxicity and high surface area offer the possibility of developing smart nanosystems for biomedical applications through the simultaneous functionalization of their structure with biologically relevant ligands and the loading of biologically active cargos, ranging from small drugs to large biomacromolecules, into their pores. Aiming to develop efficient, naturally inspired biocompatible systems, recent research has combined organic and materials chemistry to design innovative composites that exploit carbohydrate chemistry for the functionalization and structural modification of MOFs. Scientific investigation in the field has seen a significant rise in the past five years, and it is becoming crucial to acknowledge both the limits and benefits of this approach for future investigation. In this review, the latest research results merging carbohydrates and MOFs are discussed, with a particular emphasis on the advances in the field and the remaining challenges, including addressing sustainability and real-case applicability., Financial support was provided by the Andalusian Ministry of Economy, Science and Innovation in the framework of the Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI 2020, programme 54[a with combining low line] “Investigación científica e innovación,” “POSTDOC_21_00594”), the Spanish Ministry of Science and Innovation (Ref: PID2020-119949RB-I00), the Andalusian Ministry of Economy, Science and Innovation cofinanced by the European Regional Development Fund (ERDF) from FEDER and the European Social Fund (ESF) (PY20_00882 and CV20-04221). The COST action CA-18132 “Functional Glyconanomaterials for the Development of Diagnostic and Targeted Therapeutic Probe” and the COST action CA-22147 “European metal–organic framework network: combining research and development to promote technological solutions” (EU4MOFs) are also acknowledged., Peer reviewed

In this study, we present the first comparative analysis of active and passive drug delivery systems for docetaxel (DTX) in prostate cancer using supramolecular self-assembled micellar nanovectors. Specifically, we developed two novel micelles based on polydiacetylenic amphiphiles (PDA) for passive and active targeting. The active targeting micelles were designed with a prostate-specific membrane antigen (PSMA) ligand, ACUPA, to facilitate recognition by PSMA-positive cancer cells. These PDA-based micelles feature a well-defined structure with a hydrophobic PDA core and a surface functionalized with PEG, and for active targeting, ACUPA. Our micelles demonstrated excellent encapsulation capacity, significantly improving DTX solubility in water, a crucial factor for clinical drug use. In vitro studies confirmed the safety and cytotoxic profiles of both systems, with ACUPA-functionalized micelles showing notable internalization into PSMA-positive LNCaP cells, mediated through the PSMA-ACUPA interaction. In vivo imaging revealed preferential accumulation of ACUPA-functionalized nanomicelles in LNCaP xenograft tumors, suggesting enhanced retention via specific ACUPA-PSMA interactions and active uptake by LNCaP cells. Notably, Balb/c-Foxn1nu/nu early in vivo studies showed a marked reduction in tumor volume and tumor expression levels of proliferation, cell cycle progression, cell survival and anti-apoptotic markers with DTX-loaded micelles functionalized with ACUPA compared to those without ACUPA. Overall, our studies collect initial evidence regarding the feasibility of supramolecular self-assembly of ACUPA-PDA-based nanomicelles for PSMA-targeted drug chemotherapy delivery developments., Financial support was provided by the Spanish Ministry of Science and Innovation (Ref: PID2020-119949RB-I00 and PID2023-152689OB-I00 to NK; RTI2018-098432-B-100 to DP, PID2022-1381850B-I00 to RML), the Andalusian Ministry of Economy, Science and Innovation cofinanced by the European Regional Development Fund (ERDF) from FEDER and the European Social Fund (ESF) (PY20_00882 and CV20-04221 to NK, and postodoctoral fellowship “POSTDOC_21_00594” to AZ), the CSIC (CSIC-COV19-047 to NK), Andalusian Ministry of Health (PI-0232-2022 to ZGS and DP) and the PAIDI Program from the Andalusian Government (FQM-313 to NK). The COST action CA-18132 “Functional Glyconanomaterials for the Development of Diagnostic and Targeted Therapeutic Probe” is also acknowledged. ZGS holds a postdoctoral fellowship from the María Zambrano program (21-20073; Spanish Government, Ministry of Universities, NextGeneration EU). We also thank the Centre of Research Technology and Innovation of the University of Seville (CITIUS) for the use of TEM, HRMS and NMR facilities., Peer reviewed

Financial support was provided by the Andalusian Ministry of Economy, Science and Innovation in the framework of the Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI 2020, programme 54ª “Investigación científica e innovación”, “POSTDOC_21_00594”), the Spanish Ministry of Science and Innovation (Ref: PID2020-119949RB-I00), the Andalusian Ministry of Economy, Science and Innovation cofinanced by the European Regional Development Fund (ERDF) from FEDER and the European Social Fund (ESF) (PY20_00882 and CV20-04221). The COST action CA-18132 “Functional Glyconanomaterials for the Development of Diagnostic and Targeted Therapeutic Probe” is also acknowledged. The COST action CA-22147 “European metal–organic framework network: combining research and development to promote technological solutions” (EU4MOFs) is also acknowledged., Peer reviewed

ATR: Active Transport and Retention; CH2Cl2: Dichloromethane; CMC: Critical Micelle Concentration; DAPI: 4′,6-Diamidino-2-Phenylindole; DIC: N,N′-Diisopropylcarbodiimide; DLS: Dynamic Light Scattering; DMF: Dimethylformamide; DMSO: Dimethyl Sulfoxide; DXT: Docetaxel; EPR: Enhanced Permeability and Retention; FACS: Fluorescence-Activated Cell Sorting; FRUC: D-fructose; GLUT5: Glucose Transporter type 5; H&E: Haematoxylin and Eosin; HPLC: High-Performance Liquid Chromatography; HRMS: High-Resolution Mass Spectrometry; IgG: Immunoglobulin G; NMR: Nuclear Magnetic Resonance; NR: Nile Red; PDA: Polydiacetylene; PCDA: Pentacosadiynoic Acid; PEG: Polyethylene Glycol; PBS: Phosphate Buffered Saline; ROI: Region of Interest; SD: Standard Deviation; TEM: Transmission Electron Microscopy; TFA: Trifluoroacetic Acid; THF: Tetrahydrofuran; TNBC: Triple-Negative Breast Cancer., Chemicals and CAS Registry Numbers
.

azide 12596-60-0, 14343-69-2
dimethyl sulfoxide 67-68-5
docetaxel 114977-28-5
fructose 30237-26-4, 57-48-7, 7660-25-5, 77907-44-9

Show more, Triple-negative breast cancer (TNBC) is one of the most aggressive and clinically challenging subtypes of breast cancer. Its high heterogeneity and lack of actionable molecular targets limit therapeutic options, leading to poor patient outcomes. Given the reported overexpression of the fructose transporter GLUT5 (Glucose Transporter type 5) in breast cancer cells, D-fructose (FRUC) has been proposed as a ligand for active targeting; however, its effectiveness remains uncertain. Here, we investigate passive and fructose-mediated active targeting of TNBC using small-sized supramolecular micelles in vitro and in vivo. We designed two micelle formulations, one incorporating a D-fructose headgroup, using amphiphiles composed of pentacosadiynoic acid as the hydrophobic core and polyethylene glycol as a spacer. These micelles (∼10 nm) were characterized by nuclear magnetic resonance, electron microscopy, and dynamic light scattering, and their stability was confirmed under various conditions. Cellular internalization studies, flow cytometry, and confocal microscopy revealed that PEGylated micelles exhibited superior intracellular accumulation compared to fructose-functionalized micelles, suggesting that D-fructose may hinder endocytic uptake rather than enhance it. In vivo biodistribution analysis in tumor-bearing mice showed similar tumor accumulation for both formulations, with FRUC-Mic exhibiting a transiently higher presence at 1-h post-administration, though this difference was not statistically significant. Although this study does not validate D-fructose as an effective ligand for active targeting, both micelle formulations showed key advantages, including Immunoglobulin G-sized particles, high stability, and facile synthesis, enabling scalable production and clinical translation. Moreover, their ability to solubilize, stabilize, and deliver hydrophobic dyes and cytotoxic agents underscores their potential as theranostic nanoplatforms for TNBC treatment., Financial support was provided by the Spanish Ministry of Science and Innovation (Ref: PID2020-119949RB-I00 and PID2023-152689OB-I00 to NK), the Andalusian Ministry of Economy, Science and Innovation cofinanced by the European Regional Development Fund (ERDF) from FEDER and the European Social Fund (ESF) (PY20_00882, CV20-04221 and “POSTDOC_21_00594”), the CSIC (CSIC-COV19-047) the PAIDI Program from the Andalusian Government (FQM-313). The COST action CA-18132 “Functional Glyconanomaterials for the Development of Diagnostic and Targeted Therapeutic Probe” is also acknowledged. Financial support was provided by the Andalusian Ministry of Economy, Science and Innovation in the framework of the Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI 2020, programme 54a “Investigación científica e innovación”, “POSTDOC_21_00594”), the Fundación Vencer el Cancer (B.R.G. and V.C), the Spanish association against the Cancer AECC investigator grant (INVES20033COMA to V.C.) and the Marie Skłodowska-Curie Individual Fellowship (MSCA-IF Onco-inflammation 101026137 to V.C.). In vivo and ex vivo optical/X-ray images were acquired at the ICTS “NANBIOSIS”, specifically within the U28 Unit at the Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina (IBIMA Plataforma BIONAND)., Peer reviewed