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Cancer is anticipated to become the pioneer reason of disease-related deaths worldwide in the next two decades, underscoring the urgent need for personalized and adaptive treatment strategies. These strategies are crucial due to the high variability in drug efficacy and the tendency of cancer cells to develop resistance. This study investigates the potential of theranostic nanotechnology using three innovative fluorescent polymers (FP-1, FP-2, and FP-3) encapsulated in niosomal carriers, combining therapy (chemotherapy and radiotherapy) with fluorescence imaging. These cargoes are assessed for their cytotoxic effects across three cancer cell lines (A549, MCF-7, and HOb), with further analysis to determine their capacity to augment the effects of radiotherapy using a Linear Accelerator (LINAC) at specific doses. Fluorescence microscopy is utilized to verify their uptake and localization in cancerous versus healthy cell lines. The results confirmed that these niosomal cargoes not only improved the antiproliferative effects of radiotherapy but also demonstrate the practical application of fluorescent polymers in in vitro imaging. This dual function underscores the importance of dose optimization to maximize therapeutic benefits while minimizing adverse effects, thereby enhancing the overall efficacy of cancer treatments., (© 2024 The Author(s). Macromolecular Bioscience published by Wiley‐VCH GmbH.)

Delivery of proteins in plant cells can facilitate the design of desired functions by modulation of biological processes and plant traits but is currently limited by narrow host range, tissue damage, and poor scalability. Physical barriers in plants, including cell walls and membranes, limit protein delivery to desired plant tissues. Herein, a cationic high aspect ratio polymeric nanocarriers (PNCs) platform is developed to enable efficient protein delivery to plants. The cationic nature of PNCs binds proteins through electrostatic. The ability to precisely design PNCs' size and aspect ratio allowed us to find a cutoff of ≈14 nm in the cell wall, below which cationic PNCs can autonomously overcome the barrier and carry their cargo into plant cells. To exploit these findings, a reduction-oxidation sensitive green fluorescent protein (roGFP) is deployed as a stress sensor protein cargo in a model plant Nicotiana benthamiana and common crop plants, including tomato and maize. In vivo imaging of PNC-roGFP enabled optical monitoring of plant response to wounding, biotic, and heat stressors. These results show that PNCs can be precisely designed below the size exclusion limit of cell walls to overcome current limitations in protein delivery to plants and facilitate species-independent plant engineering., (© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH.)

This study explores various aspects of Metal-Organic Frameworks (MOFs), focusing on synthesis techniques to adjust pore size and key ligands and metals for crafting carrier MOFs. It investigates MOF-drug interactions, including hydrogen bonding, van der Waals, and electrostatic interactions, along with kinetic studies. The multifaceted applications of MOFs in drug delivery systems are elucidated. The morphology and structure of MOFs are intricately linked to synthesis methodology, impacting attributes like crystallinity, porosity, and surface area. Hydrothermal synthesis yields MOFs with high crystallinity, suitable for catalytic applications, while solvothermal synthesis generates MOFs with increased porosity, ideal for gas and liquid adsorption. Understanding MOF-drug interactions is crucial for optimizing drug delivery, affecting charge capacity, stability, and therapeutic efficacy. Kinetic studies determine drug release rates and uniformity, vital for controlled drug delivery. Overall, comprehending drug-MOF interactions and kinetics is essential for developing effective and controllable drug delivery systems., (© 2024 Wiley-VCH GmbH.)

Poly (β-amino ester) (PBAE) is a class of biodegradable polymers containing ester bonds in their main chain, extensively investigated as cationic polymer carriers for siRNA. Most current PBAE carriers rely on termination with hydrophilic or charged amines. In this study, a polymer platform consisting of 168 PBAE polymers with hydrophobic alkyl chain terminals is constructed through sequential aza-Michael addition. A large number of effective carriers are identified through in vitro screening of the PBAE platform for siLuc delivery to HeLa-Luc cells. Specifically, PA8-C6 and PA8-C8 achieve remarkable gene knockdown efficacies of up to 80% with low cytotoxicity. Certain materials from the PA2 and PA5 series demonstrate potent siRNA delivery capabilities associated with elevated cytotoxicity. The pKa value of PBAE is predominantly determined by the hydrophilic amine side chains rather than the end-capping groups. A pKa range of ≈6.2-6.5 may contribute to the excellent delivery capability for PA8 series carriers. The co-formulation of PBAE carriers with helper lipids leads to the reduced size and surface charges of the polyplex NPs with siRNA, consequently decreasing the cytotoxicity and enhancing siRNA delivery efficacy. These findings hold significant implications for the development of novel degradable polymer carriers for siRNA delivery., (© 2024 Wiley‐VCH GmbH.)

Micro/nanomotors represent a promising class of drug delivery carriers capable of converting surrounding chemical or external energy into mechanical power, enabling autonomous movement. Their distinct autonomous propulsive force distinguishes them from other carriers, offering significant potential for enhancing drug penetration across cellular and tissue barriers. A comprehensive understanding of micro/nanomotor dynamics with various power sources is crucial to facilitate their transition from proof-of-concept to clinical application. In this review, micro/nanomotors are categorized into three classes based on their energy sources: endogenously stimulated, exogenously stimulated, and live cell-driven. The review summarizes the mechanisms governing micro/nanomotor movements under these energy sources and explores factors influencing autonomous motion. Furthermore, it discusses methods for controlling micro/nanomotor movement, encompassing aspects related to their structure, composition, and environmental factors. The remarkable propulsive force exhibited by micro/nanomotors makes them valuable for significant biomedical applications, including tumor therapy, bio-detection, bacterial infection therapy, inflammation therapy, gastrointestinal disease therapy, and environmental remediation. Finally, the review addresses the challenges and prospects for the application of micro/nanomotors. Overall, this review emphasizes the transformative potential of micro/nanomotors in overcoming biological barriers and enhancing therapeutic efficacy, highlighting their promising clinical applications across various biomedical fields., (© 2024 Wiley‐VCH GmbH.)

Combination therapy using photothermal therapy (PTT) and immunotherapy is one of the most promising approaches for eliciting host immune responses to ablate tumors. However, its therapeutic efficacy is limited due to inefficient immune cell infiltration and cellular immune responses. In this study, a biomimetic immunostimulatory nanomodulator, Tm@PDA-GA (4T1 membrane@polydopamine-gambogic acid), with homologous targeting is developed. The 4T1 membrane (Tm) coating reduced immunogenicity and facilitated uptake of Tm@PDA-GA by tumor cells. Polydopamine (PDA) as a drug carrier can induce PTT under near-infrared ray (NIR) irradiation and immunogenic cell death (ICD) to activate dendritic cells (DCs). Moreover, Tm@PDA-GA on-demand released gambogic acid (GA) in an acidic tumor microenvironment, inhibiting the expression of heat shock proteins (HSPs) for synergetic chemo-photothermal anti-tumor activity and increasing the ICD of 4T1 cells. More importantly, GA can normalize the vessels via HIF-1α and VEGF inhibition to enhance immune infiltration and alleviate hypoxia stress. Thus, Tm@PDA-GA induced ICD, activated DCs, stimulated cytotoxic T cells, and suppressed Tregs. Moreover, Tm@PDA-GA is combined with anti-PD-L1 to further augment the tumor immune response and effectively suppress tumor growth and lung metastasis. In conclusion, biomaterial-mediated PTT combined with vessel normalization is a promising strategy for effective immunotherapy of triple-negative breast cancer (TNBC)., (© 2024 Wiley‐VCH GmbH.)

The irregular expression or activity of enzymes in the human body leads to various pathological disorders and can therefore be used as an intrinsic trigger for more precise identification of disease foci and controlled release of diagnostics and therapeutics, leading to improved diagnostic accuracy, sensitivity, and therapeutic efficacy while reducing systemic toxicity. Advanced synthesis strategies enable the preparation of polymers with enzymatically activatable skeletons or side chains, while understanding enzymatically responsive mechanisms promotes rational incorporation of activatable units and predictions of the release profile of diagnostics and therapeutics, ultimately leading to promising applications in disease diagnosis and treatment with superior biocompatibility and efficiency. By overcoming the challenges, new opportunities will emerge to inspire researchers to develop more efficient, safer, and clinically reliable enzymatically activatable polymeric carriers as well as prodrugs., (© 2023 Wiley‐VCH GmbH.)

Endosome is a major barrier in the intracellular delivery of drugs, especially for biologics, such as proteins, peptides, and nucleic acids. After being endocytosed, these cargos will be trapped inside the endosomal compartments and finally degraded in the lysosomes. Thus, various strategies have been developed to facilitate the escape of cargos from the endosomes to improve the intracellular delivery efficiency. While the majority of the studies are focusing on strengthening the endosomal escape capability to maximize the delivery outcome, recent evidence suggests that a careful control of the endosomal escape process could provide opportunity for targeted drug delivery. In this concept review, we examined current delivery systems that can sense intra-endosomal factors or external stimuli for controlling endosomal escape toward a targeted intracellular delivery of cargos. Furthermore, the prospects and challenges of such strategies are discussed., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

In recent years, nanoparticles based on cyclodextrins have been widely investigated, mainly for drug delivery. In this work, we synthesized nanoparticles with a hyaluronic acid backbone (11 kDa and 45 kDa) functionalized with γ-cyclodextrins. We tested sorafenib in the presence of the new hyaluronan-cyclodextrin conjugates in A2780 (ovarian cancer), SK-HeP-1 (adenocarcinoma) and MDA-MB-453 (breast cancer) cell lines. We found that hyaluronan-cyclodextrin conjugates improve the antiproliferative activity of sorafenib. Remarkably, the system based on the 11 kDa hyaluronan conjugate was the most effective and, in the MDA-MB-453 cell line, significantly reduced the IC 50 value of sorafenib cells by about 75 %., (© 2024 Wiley-VCH GmbH.)

Supramolecular gels are an important class of materials that are promising for its wide range of applications including drug delivery. While supramolecular gels are intrinsically porous because of the 3D nano-matrix (gel matrix) that is being formed due to supramolecular self-assembly process involving the gelator molecules during gelation, additional nanopores can be introduced to the overall gel if the gelator molecule itself holds molecular cavity such as metal-organic-cage (MOC) molecules. A MOC having the molecular formula [(Pd 2 L2 4 ).4NO 3 ].3H 2 O.2DMF.MeOH (Pd-cage) (L2=5-Azido-N,N'-di-pyridin-3-yl-isophthalamide) was successfully synthesized and characterized by FT-IR, 1 H NMR, ESI-MS and single crystal X-ray diffraction. Stimuli-reversible supramolecular metallogel PdG could easily be formed from Pd-cage in DMSO/water mixture. The molecular cage of Pd-cage was demonstrated to be available for loading an anti-cancer drug namely doxorubicin (DOX). Subsequently, DOX was also loaded within PdG and delivered to melanoma cell line B16-F10 displaying significant anti-cancer activity as revealed by both MTT and scratch assay. Rheoreversibility of PdG and its ability to load and deliver DOX to cancer cells clearly raised hope for developing this metallogel further as topical anticancer gel., (© 2024 Wiley-VCH GmbH.)

Gastric ulcers are characterized by damage to the stomach lining and are often triggered by substances such as ethanol and non-steroidal anti-inflammatory drugs. Patchouli alcohol (PA) has demonstrated effectiveness in treating gastric ulcers through antioxidative and anti-inflammatory effects. However, the water insolubility of PA and rapid gastric emptying cause low drug concentration and poor absorption in the stomach, resulting in limited treatment efficacy of PA. This study develops an oral gastroretentive raft forming system (GRFDDS) containing the aminated hollow mesoporous silica nanoparticles (NH 2 -HMSN) for PA delivery. The application of NH 2 -HMSN can enhance PA-loading capacity and water dispersibility, promoting bio-adhesion to the gastric mucosa and sustained drug release. The incorporation of PA-loaded NH 2 -HMSN (NH 2 -HMSN-PA) into GRFDDS can facilitate gastric drug retention and achieve long action, thereby improving therapeutic effects. The results reveal that NH 2 -HMSN-PA protects the gastric mucosa damage by inhibiting NLRP3-mediated pyroptosis. The GRFDDS, optimized through orthogonal design, demonstrates the gastric retention capacity and sustained drug release, exhibiting significant therapy efficacy in an ethanol-induced acute gastric ulcers model and an aspirin-induced chronic gastric ulcers model through antioxidation, anti-pyroptosis, and anti-inflammation. This study provides a potential strategy for enhancing druggability of insoluble natural compounds and therapeutic management of gastric ulcers., (© 2024 Wiley‐VCH GmbH.)

The ubiquitous mold Aspergillus fumigatus (A. fumigatus) is one of the main fungal pathogens causing invasive infections in immunocompromised humans. Conventional antifungal agents exhibit limited efficacy and often cause severe side effects. Nanoparticle-based antifungal delivery provides a promising alternative, which can increase local drug concentration; while, mitigating toxicity, thereby enhancing treatment efficacy. Previous research underscores the potential of poly(glycidol)-based nanogels (NG) with negative surface charge as carriers for delivering antifungals to A. fumigatus hyphae. In this study, NG is tailored with 2-carboxyethyl acrylate (CEA) or with phosphoric acid 2-hydroxyethyl acrylate (PHA). It is discovered that quenching with PHA clearly improves the adhesion of NG to hyphal surface and the internalization of NG into the hyphae under protein-rich conditions, surpassing the outcomes of non-quenched and CEA-quenched NG. This enhancement cannot be solely attributed to an increase in negative surface charge but appears to be contingent on the functional group of the quencher. Further, it is demonstrated that itraconazole-loaded, PHA-functionalized nanogels (NGxPHA-ITZ) show lower MIC in vitro and superior therapeutic effect in vivo against A. fumigatus compared to pure itraconazole. This confirms NGxPHA as a promising antifungal delivery system., (© 2024 The Author(s). Macromolecular Bioscience published by Wiley‐VCH GmbH.)

Microplastic pollution and the urgent need for sustainable agriculture have raised interest in developing degradable carriers for controlled agrochemical release. Porous polymeric particles are particularly promising due to their unique release profiles compared to solid or core-shell carriers. However, creating degradable, mesoporous (2-50 nm) microparticles is challenging, and their potential for agrochemical delivery is largely unexplored. A straightforward self-assembly method is demonstrated for fully degradable porous polymer cubosomes (PCs), showcasing their ability to load and release agrochemicals. Using fully degradable block copolymers (BCPs), poly(ethyl ethylene phosphate)-b-polylactide (PEEP-b-PLA), PCs are synthesized in water with high inner order and open pores averaging 19 ± 3 nm in diameter. During the self-assembly process in the presence of the hydrophobic fungicide tebuconazole, polymersomes transform into PCs by enriching the hydrophobic polymer domain and altering the BCP packing parameter. After self-assemby, highly porous and fungicide-loaded PCs are obtained. Fungicide-loaded PCs show high antimycotic activity against Botrytis cinerea (grey mold), adhere to Vitis vinifera Riesling leaves even after simulated rain, and release the fungicide continuously over several days with different release-kinetics compared to solid particles. PCs hydrolyze completely into lactic acid and phosphate derivatives, highlighting their potential as microplastic-free agrochemical delivery systems for sustainable agriculture., (© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH.)

In recent years, multifunctional nanocarriers that provide simultaneous drug delivery and imaging have attracted enormous attention, especially in cancer treatment. In this research, a biocompatible fluorescent multifunctional nanocarrier is designed for the co-delivery of capsaicin (CPS) and nitrogen-doped graphene quantum dots (N-GQDs) using the pH sensitive amphiphilic block copolymer (poly(2-ethyl-2-oxazoline)-b-poly(ε-caprolactone), PEtOx-b-PCL). The effects of the critical formulation parameters (the amount of copolymer, the concentration of poly(vinyl alcohol) (PVA) as a stabilizing agent in the inner aqueous phase, and volume of the inner phase) are evaluated to achieve optimal nanoparticle (NP) properties using Central Composite Design. The optimized NPs demonstrated a desirable size distribution (167.8 ± 1.4 nm) with a negative surface charge (-19.9 ± 0.4) and a suitable loading capacity for CPS (70.80 ± 0.05%). The CPS & N-GQD NPs are found to have remarkable toxicity on human breast adenocarcinoma cell line (MCF-7). The solid fluorescent signal is acquired from cells containing multifunctional NPs, according to the confocal microscope imaging results, confirming the significant cellular uptake. This research illustrates the enormous potential for cellular imaging and enhanced cancer therapy offered by multifunctional nanocarriers that combine drug substances with the novel fluorescent agents., (© 2024 The Author(s). Macromolecular Bioscience published by Wiley‐VCH GmbH.)

Intra-articular injection of drugs is an effective strategy for osteoarthritis (OA) treatment. However, the complex microenvironment and limited joint space result in rapid clearance of drugs. Herein, a nanogel-based strategy is proposed for prolonged drug delivery and microenvironment remodeling. Nanogel is constructed through the functionalization of hyaluronic acid (HA) by amide reaction on the surface of Kartogenin (KGN)-loaded zeolitic imidazolate framework-8 (denoted as KZIF@HA). Leveraging the inherent hydrophilicity of HA, KZIF@HA spontaneously forms nanogels, ensuring extended drug release in the OA microenvironment. KZIF@HA exhibits sustained drug release over one month, with low leakage risk from the joint cavity compared to KZIF, enhanced cartilage penetration, and reparative effects on chondrocytes. Notably, KGN released from KZIF@HA serves to promote extracellular matrix (ECM) secretion for hyaline cartilage regeneration. Zn 2+ release reverses OA progression by promoting M2 macrophage polarization to establish an anti-inflammatory microenvironment. Ultimately, KZIF@HA facilitates cartilage regeneration and OA alleviation within three months. Transcriptome sequencing validates that KZIF@HA stimulates the polarization of M2 macrophages and secretes IL-10 to inhibit the JNK and ERK pathways, promoting chondrocytes recovery and enhancing ECM remodeling. This pioneering nanogel system offers new therapeutic opportunities for sustained drug release, presenting a significant stride in OA treatment strategies., (© 2024 Wiley‐VCH GmbH.)

Stimuli-responsive low molecular weight hydrogel interventions for Biomedical challenges are a rapidly evolving paradigm in the bottom-up approach recently. Peptide-based self-assembled nano biomaterials present safer alternatives to their non-degradable counterparts as demanded for today's most urged clinical needs.Although a plethora of work has already been accomplished, programming hydrogelators with appropriate functionalities requires a better understanding as the impact of the macromolecular structure of the peptides and subsequently, their self-assembled nanostructures remain unidentified. Henceforth this review focuses on two aspects: Firstly, the underlying guidelines for building biomimetic strategies to tailor scaffolds leading to hydrogelation along with the role of non-covalent interactions that are the key components of various self-assembly processes. In the second section, it is aimed to bring together the recent achievements with designer assembly concerning their self-aggregation behaviour and applications mainly in the biomedical arena like drug delivery carrier design, antimicrobial, anti-inflammatory as well as wound healing materials. Furthermore, it is anticipated that this article will provide a conceptual demonstration of the different approaches taken towards the construction of these task-specific designer hydrogels. Finally, a collective effort among the material scientists is required to pave the path for the entrance of these intelligent materials into medicine from bench to bedside., (© 2024 Wiley‐VCH GmbH.)

As the core index, how to improve bioavailability of loaded cargoes is a hot topic of drug carriers. In this study, aminated β-cyclodextrin (β-CD) as a cross-linking points is first integrated into 3D poly(acrylamide-co-acrylonitrile) (P(AAm-co-AN)) network to build up a unique submicrocage (466.2 ± 47.6 nm), featuring upper critical solution temperature (UCST; ≈40 °C), high volume expansion coefficient, and excellent biocompatibility. Hereinto, hydrophobic β-elemene (ELE) is locally loaded in β-CD with high loading efficiency (8.72%) and encapsulation efficiency (78.60%) through hydrophobic desolvation and host-guest interaction. Above UCST, the release of the loaded ELE is accelerated to 72.87% in 24 h, together with the enhanced sensitization effect of synergized radiotherapy. Given spontaneous long-lasting delivery, targeted embolization, and post-treatment removal of such UCST-type submicrocage, it is anticipated to provide a novel, facile, efficient, and versatile strategy of comprehensive anticancer treatments for high drug bioavailability., (© 2024 Wiley‐VCH GmbH.)

Current research in cancer therapy focuses on personalized therapies, through nanotechnology-based targeted drug delivery systems. Particularly, controlled drug release with nanoparticles (NPs) can be designed to safely transport various active agents, optimizing delivery to specific organs and tumors, minimizing side effects. The use of microfluidics (MFs) in this field has stood out against conventional methods by allowing precise control over parameters like size, structure, composition, and mechanical/biological properties of nanoscale carriers. This review compiles applications of microfluidics in the production of core-shell NPs (CSNPs) for cancer therapy, discussing the versatility inherent in various microchannel and/or micromixer setups and showcasing how these setups can be utilized individually or in combination, as well as how this technology allows the development of new advances in more efficient and controlled fabrication of core-shell nanoformulations. Recent biological studies have achieved an effective, safe, and controlled delivery of otherwise unreliable encapsulants such as small interfering RNA (siRNA), plasmid DNA (pDNA), and cisplatin as a result of precisely tuned fabrication of nanocarriers, showing that this technology is paving the way for innovative strategies in cancer therapy nanofabrication, characterized by continuous production and high reproducibility. Finally, this review analyzes the technical, biological, and technological limitations that currently prevent this technology from becoming the standard., (© 2024 The Authors. Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

In this work, the synthesis of core-shell ordered mesoporous silica nanoparticles (CSMS) with tunable particle size and shape through a dual surfactant-assisted approach is demonstrated. By varying the synthesis conditions, including the type of the solvent and the concentration of the surfactant, monodispersed and ordered mesoporous silica nanoparticles with tunable particle size (140-600 nm) and morphologies (hexagonal prism (HP), oblong, spherical, and hollow-core) can be realized. Comparative studies of the Cabazitaxel (CBZ)-loaded HP and spherical-shaped CSMS are conducted to evaluate their drug delivery efficiency to PC3 (prostate cancer) cell lines. These nanoparticles showed good biocompatibility and displayed a faster drug release at acidic pH than at basic pH. The cellular uptake of CSMS measured using confocal microscopy, flow cytometry, microplate reader, and ICP-MS (inductively coupled plasma mass spectrometry) techniques in PC3 cell lines revealed a better uptake of CSMS with HP morphology than its spherical counterparts. Cytotoxicity study showed that the anticancer activity of CBZ is improved with a higher free radical production when loaded onto CSMS. These unique materials with tunable morphology can serve as an excellent drug delivery system and will have potential applications for treating various cancers., (© 2023 The Authors. Small published by Wiley‐VCH GmbH.)

Innovative silica nanomaterials have made the significant advancements in curative therapy against cancers with multidrug resistance (MDR). The study on different-nanostructured mesoporous silica nanoparticles (MSNs) with discrepant pore sizes affecting biomacromolecules in resisting cancer MDR hasn't been reported yet. In this study, a systematic comparison of 6 nm-pore sized hollow-structured MSNs (HMSNs) and 10 nm-pore sized dendrimers-structured MSNs (LMSNs) for delivering Bcl-2-functional converting peptide (N9) or doxorubicin (DOX) to overcome cancer MDR is comprehensively carried out both in in vitro and in vivo resistant tumor models. The results show that both LMSNs and HMSNs exert no significant difference in delivering DOX to treat drug-resistant cancers. However, compared with N9@HMSNs, N9@LMSNs display the increased loading efficiency, the improved cell-penetrative capability, the higher cancer cell apoptosis effect, the enhanced tumor accumulation and retention efficiency, and the final elevated tumor inhibition efficiency. Unexpectedly, naked LMSNs without surface modification especially at high dosage produce relatively more serious toxicity than HMSNs whatever in cells, zebrafish embryo or mice models. Collectively, the data provide the sufficient theoretical evidence that LMSNs might be a better choice for delivering biomacromolecules to treat resistant cancers after appropriate surface functionalization such as with PEGylation to weaken its intrinsic toxicity., (© 2024 Wiley‐VCH GmbH.)

Efficient and site-specific delivery of therapeutics drugs remains a critical challenge in cancer treatment. Traditional drug nanocarriers such as antibody-drug conjugates are not generally accessible due to their high cost and can lead to serious side effects including life-threatening allergic reactions. Here, these problems are overcome via the engineering of supramolecular agents that are manufactured with an innovative double imprinting approach. The developed molecularly imprinted nanoparticles (nanoMIPs) are targeted toward a linear epitope of estrogen receptor alfa (ERα) and loaded with the chemotherapeutic drug doxorubicin. These nanoMIPs are cost-effective and rival the affinity of commercial antibodies for ERα. Upon specific binding of the materials to ERα, which is overexpressed in most breast cancers (BCs), nuclear drug delivery is achieved via receptor-mediated endocytosis. Consequentially, significantly enhanced cytotoxicity is elicited in BC cell lines overexpressing ERα, paving the way for precision treatment of BC. Proof-of-concept for the clinical use of the nanoMIPs is provided by evaluating their drug efficacy in sophisticated three-dimensional (3D) cancer models, which capture the complexity of the tumor microenvironment in vivo without requiring animal models. Thus, these findings highlight the potential of nanoMIPs as a promising class of novel drug compounds for use in cancer treatment., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Cancer is one of the deadliest diseases worldwide. One of the most commonly applied therapeutic techniques to combat this disease is chemotherapy. Despite its success, the majority of clinically applied chemotherapeutic agents are associated with strong side effects and drug resistance. To overcome this limitation, much research efforts are devoted toward the development of new anticancer agents. Among the most promising class of compounds, Cu(II) complexes have emerged. Despite their strong cytotoxic effect, these agents are typically associated with low water solubility, low stability, and poor tumor selectivity. To overcome these limitations, herein, we report on the encapsulation of a promising Cu(II) terpyridine complex with the Pluronic F-127/Poloxamer-407 polymeric carrier into nanoparticles. Besides overcoming the pharmacological drawbacks, the nanoparticles were able to eradicate human breast adenocarcinoma monolayer cells as well as challenging multicellular tumor spheroids at nanomolar concentrations., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Chemotherapy is one of the most employed strategies in clinical treatment of cancer. However, reducing medication adverse effects and improving the biological activity remains a significant issue for chemotherapy. We developed a pH and Ca 2+ -responsive pillar[5]arene-based supramolecular nanodrug delivery system (NDDS) WP5⊃EV@DOX to address the aforementioned challenges. The formation of this NDDS began with the spontaneous formation of supramolecular nanodrug carrier WP5⊃EV in water from PEG-modified pillar[5]arene and the bipyridilium salt derivative EV through simple host-guest interaction. Then the antitumor drug doxorubicin DOX was efficiently loaded with a high encapsulation rate of 84.6 %. Cytotoxicity results indicated that the constructed nanoplatform not only reduced DOX toxicity and side effects on normal cell (293T), but also significantly enhanced the antitumor activity on cancer cell (HepG2). Moreover, in vivo experiments showed that WP5⊃EV@DOX had a longer half-life and higher bioavailability in the blood of mice compared to the nake drug DOX, with increases to 212 % and 179 %, respectively. Therefore, WP5⊃EV@DOX has great potential in tumor therapy and provides a new idea for host-guest drug delivery system., (© 2024 Wiley-VCH GmbH.)

Nanoscale Metal-Organic Frameworks (nanoMOFs) are widely implemented in a host of assays involving drug delivery, biosensing catalysis, and bioimaging. However, the cell pathways and cell fate remain poorly understood. Here, a new fluorescent nanoMOF integrating ATTO 655 into surface defects of colloidal UiO-66 is synthesized, allowing to track the spatiotemporal localization of Single nanoMOF in live cells. Density functional theory reveals the stronger binding of ATTO 655 to the Zr 6 cluster nodes compared with phosphate and Alendronate Sodium. Parallelized tracking of the spatiotemporal localization of thousands of nanoMOFs and analysis using machine learning platforms reveals whether nanoMOFs remain outside as well as their cellular internalization pathways. To quantitatively assess their colocalization with endo/lysosomal compartments, a colocalization proxy approach relying on the nanoMOF detection of particles in one channel to the signal in the corresponding endo/lysosomal compartments channel, considering signal versus local background intensity ratio and signal-to-noise ratio is developed. This strategy mitigates colocalization value inflation from high or low signal expression in endo/lysosomal compartments. The results accurately measure the nanoMOFs' colocalization from early to late endosomes and lysosomes and emphasize the importance of understanding their intracellular dynamics based on single-particle tracking for optimal and safe drug delivery., (© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH.)

Supramolecular self-assembly has emerged as an efficient tool to construct well-organized nanostructures for biomedical applications by small organic molecules. However, the physicochemical properties of self-assembled nanoarchitectures are greatly influenced by their morphologies, mechanical properties, and working mechanisms, making it challenging to design and screen ideal building blocks. Herein, using a biocompatible firefly-sourced click reaction between the cyano group of 2-cyano-benzothiazole (CBT) and the 1,2-aminothiol group of cysteine (Cys), an amino-acid-encoded supramolecular self-assembly platform Cys(SEt)-X-CBT (X represents any amino acid) is developed to incorporate both covalent and noncovalent interactions for building diverse morphologies of nanostructures with bioinspired response mechanism, providing a convenient and rapid strategy to construct site-specific nanocarriers for drug delivery, cell imaging, and enzyme encapsulation. Additionally, it is worth noting that the biodegradation of Cys(SEt)-X-CBT generated nanocarriers can be easily tracked via bioluminescence imaging. By caging either the thiol or amino groups in Cys with other stimulus-responsive sites and modifying X with probes or drugs, a variety of multi-morphological and multifunctional nanomedicines can be readily prepared for a wide range of biomedical applications., (© 2024 Wiley‐VCH GmbH.)

Pathological ocular neovascularization resulting from retinal ischemia constitutes a major cause of vision loss. Current anti-VEGF therapies rely on burdensome intravitreal injections of Bevacizumab (Beva). Herein ultrasmall polymeric micelles encapsulating Beva (P@Beva) are developed for noninvasive topical delivery to posterior eye tissues. Beva is efficiently loaded into 11 nm micelles fabricated via self-assembly of hyperbranched amphiphilic copolymers. The neutral, brush-like micelles demonstrate excellent drug encapsulation and colloidal stability. In vitro, P@Beva enhances intracellular delivery of Beva in ocular cells versus free drug. Ex vivo corneal and conjunctival-sclera-choroidal tissues transport after eye drops are improved 23-fold and 7.9-fold, respectively. Anti-angiogenic bioactivity is retained with P@Beva eliciting greater inhibition of endothelial tube formation and choroid sprouting over Beva alone. Remarkably, in an oxygen-induced retinopathy (OIR) model, topical P@Beva matching efficacy of intravitreal Beva injection, is the clinical standard. Comprehensive biocompatibility verifies safety. Overall, this pioneering protein delivery platform holds promise to shift paradigms from invasive intravitreal injections toward simplified, noninvasive administration of biotherapeutics targeting posterior eye diseases., (© 2024 Wiley‐VCH GmbH.)

The next generation of anticancer agents are emerging from rationally designed nanostructured materials. This work involved the synthesis and characterization of novel hollow DNA-conjugated gold nanoparticles (DNA-AuNPs) for controlled drug delivery. Polyethyleneimine (PEI) was bound to AuNPs, forming polymer-shell nanoparticles. Dissolution of the gold core via iodine formed hollow core polymeric nanoparticles (HCPNPs) and a high density (85 molecules/particle) of DNA intercalated with daunorubicin was conjugated. Particles were spherical with an average diameter of 105.7±17.3 nm and zeta potential of 20.4±3.54 mV. We hypothesize the DNA backbone electrostatically condensed to the primary amines on the surface of the particle toroidally, weaving itself within the polymer shell. During the DNA intercalation process, increasing the ionic concentration and decreasing the amine/phosphate ratio 10-fold increased drug intercalation 64 % and 61 %, respectively, allowing us to determine the optimal method of particle synthesis. As intercalation sites increased with increasing DNA strand length, drug loading increased. An average of 874±40.1 daunorubicin molecules were loaded per HCPNP. HCPNPs with drug intercalated DNA have strong potential to be clinically efficacious drug delivery vehicles due to the versatility of DNA and high drug loading capacities., (© 2024 The Authors. ChemPlusChem published by Wiley-VCH GmbH.)

Protein therapeutics are anticipated to offer significant treatment options for central nervous system (CNS) diseases. However, the majority of proteins are unable to traverse the blood-brain barrier (BBB) and reach their CNS target sites. Inspired by the natural environment of active proteins, the cell matrix components hyaluronic acid (HA) and protamine (PRTM) are used to self-assemble with proteins to form a protein-loaded biomimetic core and then incorporated into ApoE3-reconstituted high-density lipoprotein (rHDL) to form a protein-loaded biomimetic nanocarrier (Protein-HA-PRTM-rHDL). This cell matrix-inspired biomimetic nanocarrier facilitates the penetration of protein therapeutics across the BBB and enables their access to intracellular target sites. Specifically, CAT-HA-PRTM-rHDL facilitates rapid intracellular delivery and release of catalase (CAT) via macropinocytosis-activated membrane fusion, resulting in improved spatial learning and memory in traumatic brain injury (TBI) model mice (significantly reduces the latency of TBI mice and doubles the number of crossing platforms), and enhances motor function and prolongs survival in amyotrophic lateral sclerosis (ALS) model mice (extended the median survival of ALS mice by more than 10 days). Collectively, this cell matrix-inspired nanoplatform enables the efficient CNS delivery of protein therapeutics and provides a novel approach for the treatment of CNS diseases., (© 2024 Wiley‐VCH GmbH.)

Polymeric micelles with a hydrophobic core represent versatile nanostructures for encapsulation and delivery of water-insoluble drugs. Here, water-insoluble beclometasone dipropionate (BDP) which is a potent anti-inflammatory therapeutic agent but limited to topical applications so far, is encapsulated. Therefore, this work used an amphiphilic block copolymer self-assembling into flexible polymeric filomicelles, which have recently proven to selectively target inflamed areas in patients with inflammatory bowel disease (IBD). The small diameter and flexibility of these filomicelles is considered beneficial for transepithelial passages, while their length minimizes the unspecific uptake into nontargeted cells. This work successfully establishes a protocol to load the water-insoluble BDP into the core of the filomicelles, while maintaining the particle stability to prevent any premature drug release. The anti-inflammatory efficacy of BDP-loaded filomicelles is further investigated on lipopolysaccharide (LPS) stimulated human monocytes. In these ex vivo assays, the BDP-loaded filomicelles significantly reduce TNF-α, IL-6, IL-1ß, IL-12p70, IL-17a, and IL-23 release after 24 h. Additional time course study of drug-loaded filomicelles and their comparison with a common water-soluble and unspecific corticosteroid demonstrate promising results with significant immune response suppression in stimulated monocytes after 2 and 6 h. These findings demonstrate the potential of polymeric filomicelles as a vehicle for potent water-insoluble corticosteroids., (© 2024 The Author(s). Macromolecular Bioscience published by Wiley‐VCH GmbH.)

Solid nanoparticle-mediated drug delivery systems are usually confined to nanoscale due to the enhanced permeability and retention effect. However, they remain a great challenge for malignant glioma chemotherapy because of poor drug delivery efficiency and insufficient tumor penetration resulting from the blood-brain barrier/blood-brain tumor barrier (BBB/BBTB). Inspired by biological microparticles (e.g., cells) with excellent adaptive deformation, it is demonstrated that the adaptive microdrugs (even up to 3.0 µm in size) are more efficient than their nanodrugs (less than 200 nm in size) to cross BBB/BBTB and penetrate into tumor tissues, achieving highly efficient chemotherapy of malignant glioma. The distinct delivery of the adaptive microdrugs is mainly attributed to the enhanced interfacial binding and endocytosis via adaptive deformation. As expected, the obtained adaptive microdrugs exhibit enhanced accumulation, deep penetration, and cellular internalization into tumor tissues in comparison with nanodrugs, significantly improving the survival rate of glioblastoma mice. It is believed that the bioinspired adaptive microdrugs enable them to efficiently cross physiological barriers and deeply penetrate tumor tissues for drug delivery, providing an avenue for the treatment of solid tumors., (© 2024 Wiley‐VCH GmbH.)

Lipidic nanocarriers are a broad class of lipid-based vectors with proven potential for packaging and delivering emerging nucleic acid therapeutics. An important early step in the clinical development cycle is large-scale screening of diverse formulation libraries to assess particle quality and payload delivery efficiency. Due to the size of the screening space, this process can be both costly and time-consuming. To address this, computational models capable of predicting clinically relevant physio-chemical properties of dendrimer-lipid nanocarriers, along with their mRNA payload delivery efficiency in human cells are developed. The models are then deployed on a large theoretical nanocarrier pool consisting of over 4.5 million formulations. Top predictions are synthesised for validation using cell-based assays, leading to the discovery of a high quality, high performing, candidate. The methods reported here enable rapid, high-throughput, in silico pre-screening for high-quality candidates, and have great potential to reduce the cost and time required to bring mRNA therapies to the clinic., (© 2024 Nuntius Therapeutics. Advanced Science published by Wiley‐VCH GmbH.)

Photochemical internalization is an efficient strategy relying on photodynamic reactions to promote siRNA endosomal escape for the success of RNA-interference gene regulation, which makes gene-photodynamic combined therapy highly synergistic and efficient. However, it is still desired to explore capable carriers to improve the delivery efficiency of the immiscible siRNA and organic photosensitizers simultaneously. Herein, we employ a micellar nanostructure (PSNA) self-assembled from polymer-DNA molecular chimeras to fulfill this task. PSNA can plentifully load photosensitizers in its hydrophobic core simply by the nanoprecipitation method. Moreover, it can organize siRNA self-assembly by the densely packed DNA shell, which leads to a higher loading capacity than the typical electrostatic condensation method. The experimental results prove that this PSNA carrier can greatly facilitate siRNA escape from the endosome/lysosome and enhance transfection. Accordingly, the PSNA-administrated therapy exhibits a significantly improved anti-tumor efficacy owing to the highly efficient co-delivery capability., (© 2024 Wiley-VCH GmbH.)

In the realm of cancer therapy, the spotlight is on nanoscale pharmaceutical delivery systems, especially polymer-based nanoparticles, for their enhanced drug dissolution, extended presence in the bloodstream, and precision targeting achieved via surface engineering. Leveraging the amplified permeation and retention phenomenon, these systems concentrate therapeutic agents within tumor tissues. Nonetheless, the hurdles of systemic toxicity, biological barriers, and compatibility with living systems persist. Fluorinated polymers, distinguished by their chemical idiosyncrasies, are poised for extensive biomedical applications, notably in stabilizing drug metabolism, augmenting lipophilicity, and optimizing bioavailability. Material science heralds the advent of fluorinated polymers that, by integrating fluorine atoms, unveil a suite of drug delivery merits: the hydrophobic traits of fluorinated alkyl chains ward off lipid or protein disruption, the carbon-fluorine bond's stability extends the drug's lifecycle in the system, and a lower alkalinity coupled with a diminished ionic charge bolsters the drug's ability to traverse cellular membranes. This comprehensive review delves into the utilization of fluorinated polymers for oncological pharmacotherapy, elucidating their molecular architecture, synthetic pathways, and functional attributes, alongside an exploration of their empirical strengths and the quandaries they encounter in both experimental and clinical settings., (© 2024 Wiley‐VCH GmbH.)

The in vivo fate of chemotherapeutic drugs plays a vital role in understanding the therapeutic outcome, side effects, and the mechanism. However, the lack of imaging abilities of drugs, tedious labeling processes, and premature leakage of imaging agents result in loss of fidelity between the drugs and imaging signals. Herein, an amphiphilic polymer is created by copolymerization of a near-infrared-II (NIR-II) fluorophore tracer (T) and an anticancer Pt(IV) prodrug (D) of cisplatin in a hand-holding manner into one polymer chain for the first time. The obtained Polyplatin DT is capable of delivering the drugs and the fluorophores concomitantly at a precise D/T ratio, thereby resulting in tracking the platinum drugs and even readout of them in real-time via NIR-II imaging. Polyplatin DT can self-assemble into nanoparticles, referred to as Nanoplatin DT . Furthermore, a caspase-3 cleavable peptide that serves as an apoptosis reporter is attached to Nanoplatin DT , resulting in Nanoplatin DTR that are capable of simultaneously tracking platinum drugs and evaluating the therapeutic efficacy. Overall, it is reported here the design of the first theranostic polymer with anticancer drugs, drug tracers, and drug efficacy reporters that can work in concert to provide insight into the drug fate and mechanism of action., (© 2024 Wiley‐VCH GmbH.)

Increasing the penetration and accumulation of antitumor drugs at the tumor site are crucial in chemotherapy. Smaller drug-loaded nanoparticles (NPs) typically exhibit increased tumor penetration and more effective permeation through the nuclear membrane, whereas larger drug-loaded NPs show extended retention at the tumor site. In addition, cancer stem cells (CSCs) have unlimited proliferative potential and are crucial for the onset, progression, and metastasis of cancer. Therefore, a drug-loaded amphiphilic peptide, DDP- and ATRA-loaded Pep1 (DA/Pep1), is designed that self-assembles into spherical NPs upon the encapsulation of cis-diamminedichloroplatinum (DDP) and all-trans retinoic acid (ATRA). In an acidic environment, DA/Pep1 transforms into aggregates containing sheet-like structures, which significantly increases drug accumulation at the tumor site, thereby increasing antitumor effects and inhibiting metastasis. Moreover, although DDP treatment can increase the number of CSCs present, ATRA can induce the differentiation of CSCs in breast cancer to increase the therapeutic effect of DDP. In conclusion, this peptide nanodelivery system that transforms in response to the acidic tumor microenvironment is an extremely promising nanoplatform that suggests a new idea for the combined treatment of tumors., (© 2024 Wiley‐VCH GmbH.)

Nanoparticle (NP)-based drug delivery systems are conceived to solve poor water-solubility and chemical/physical instability, and their purpose expanded to target specific sites for maximizing therapeutic effects and minimizing unwanted events of payloads. Targeted sites are also narrowed from organs/tissues and cells to cytosol/organelles. Beyond specific site targeting, the particular release of payloads at the target sites is growing in importance. This review overviews various issues and their general strategies during multiple steps, from the preparation of drug-loaded NPs to their drug release at the target cytosol/organelles. In particular, this review focuses on current strategies for "first" delivery and "later" release of drugs to the cytosol or organelles of interest using specific stimuli in the target sites. Recognizing or distinguishing the presence/absence of stimuli or their differences in concentration/level/activity in one place from those in another is applied to stimuli-triggered release via bond cleavage or nanostructural transition. In addition, future directions on understanding the intracellular balance of stimuli and their counter-stimuli are demonstrated to synergize the therapeutic effects of payloads released from stimuli-sensitive NPs., (© 2024 The Authors. Macromolecular Bioscience published by Wiley‐VCH GmbH.)

Cancer stem cells (CSCs) are one of the determinants of tumor heterogeneity and are characterized by self-renewal, high tumorigenicity, invasiveness, and resistance to various therapies. To overcome the resistance of traditional tumor therapies resulting from CSCs, a strategy of double drug sequential therapy (DDST) for CSC-enriched tumors is proposed in this study and is realized utilizing the developed double-layered hollow mesoporous cuprous oxide nanoparticles (DL-HMCONs). The high drug-loading contents of camptothecin (CPT) and all-trans retinoic acid (ATRA) demonstrate that the DL-HMCON can be used as a generic drug delivery system. ATRA and CPT can be sequentially loaded in and released from CPT3@ATRA3@DL-HMCON@HA. The DDST mechanisms of CPT3@ATRA3@DL-HMCON@HA for CSC-containing tumors are demonstrated as follows: 1) the first release of ATRA from the outer layer induces differentiation from CSCs with high drug resistance to non-CSCs with low drug resistance; 2) the second release of CPT from the inner layer causes apoptosis of non-CSCs; and 3) the third release of Cu + from DL-HMCON itself triggers the Fenton-like reaction and glutathione depletion, resulting in ferroptosis of non-CSCs. This CPT3@ATRA3@DL-HMCON@HA is verified to possess high DDST efficacy for CSC-enriched tumors with high biosafety., (© 2024 Wiley‐VCH GmbH.)

As an indispensable part of the human sensory system, visual acuity may be impaired and even develop into irreversible blindness due to various ocular pathologies. Among ocular diseases, fundus neovascularization diseases (FNDs) are prominent etiologies of visual impairment worldwide. Intravitreal injection of anti-vascular endothelial growth factor drugs remains the primary therapy but is hurdled by common complications and incomplete potency. To renovate the current therapeutic modalities, nanomedicine emerged as the times required, which is endowed with advanced capabilities, able to fulfill the effective ocular fundus drug delivery and achieve precise drug release control, thus further improving the therapeutic effect. This review provides a comprehensive summary of advances in nanomedicine for FND management from state-of-the-art studies. First, the current therapeutic modalities for FNDs are thoroughly introduced, focusing on the key challenges of ocular fundus drug delivery. Second, nanocarriers are comprehensively reviewed for ocular posterior drug delivery based on the nanostructures: polymer-based nanocarriers, lipid-based nanocarriers, and inorganic nanoparticles. Thirdly, the characteristics of the fundus microenvironment, their pathological changes during FNDs, and corresponding strategies for constructing smart nanocarriers are elaborated. Furthermore, the challenges and prospects of nanomedicine for FND management are thoroughly discussed., (© 2024 The Authors. Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Transmembrane delivery of biologically active nucleic acids is an important process in cells and has inspired one to develop advanced drug delivery techniques. In this contribution, molecular-level single-stranded nucleic acid transmembrane carriers are reported based on 3.2 nm long Huc's foldamers (A Orn Q 3 Q 3 ) 8 and ( m Q 3 Q 2 ) 8 with linearly and helically aligned positive charges, respectively. These two foldamers not only show very strong DNA affinity via electrostatic interactions but also discriminatively bind single-stranded DNA (ss-DNA) and double-stranded DNA (ds-DNA), corroborating the importance of precise charge arrangement in the electrostatic interactions. More importantly, these two foldamers are capable of efficiently transporting ss-DNA across the lipid membranes, and the ss-DNA transport activity of (A Orn Q 3 Q 3 ) 8 with linearly aligned charges is higher than that of ( m Q 3 Q 2 ) 8 with helically aligned charges. Thus a type of novel single-stranded nucleic acid transmembrane molecular carriers based on positively charged helical foldamers are introduced. Further, effective and enhanced expression in EGFP-mRNA transfection experiments strongly demonstrates the potential of positively charged foldamers for RNA transmembrane transport and therapy., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

The tumor uptake of large non-targeted nanocarriers primarily occurs through passive extravasation, known as the enhanced permeability and retention (EPR) effect. Prior studies demonstrated improved tumor uptake and retention of 4-arm 40 kDa star polyethylene glycol (StarPEG) polymers for cancer imaging by adding prostate-specific membrane antigen (PSMA) targeting small molecule ligands. To test PSMA-targeted delivery and therapeutic efficacy, StarPEG nanodrugs with/without three copies of PSMA-targeting ligands, ACUPA, are designed and synthesized. For single-photon emission computed tomography (SPECT) imaging and therapy, each nanocarrier is labeled with 177Lu using DOTA radiometal chelator. The radiolabeled nanodrugs, [177Lu]PEG-(DOTA)1 and [177Lu]PEG-(DOTA)1(ACUPA)3, are evaluated in vitro and in vivo using PSMA+ PC3-Pip and/or PSMA- PC3-Flu cell lines, subcutaneous xenografts and disseminated metastatic models. The nanocarriers are efficiently radiolabeled with 177Lu with molar activities 10.8-15.8 MBq/nmol. Besides excellent in vitro PSMA binding affinity (kD = 51.7 nM), the targeted nanocarrier, [177Lu]PEG-(DOTA)1(ACUPA)3, demonstrated excellent in vivo SPECT imaging contrast with 21.3% ID/g PC3-Pip tumors uptake at 192 h. Single doses of 18.5 MBq [177Lu]PEG-(DOTA)1(ACUPA)3 showed complete resolution of the PC3-Pip xenografts observed up to 138 days. Along with PSMA-targeted excellent imaging contrast, these results demonstrated high treatment efficacy of [177Lu]PEG-(DOTA)1(ACUPA)3 for prostate cancer, with potential for clinical translation., (© 2024 The Authors. Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

The major bottleneck in using polymer nanovectors for biomedical application, particularly those based on self-immolative poly(amino ester) (PAE), lies in their uncontrolled autodegradation at physiological pH before they can reach the intended target. Here, an elegant triblock-copolymer strategy is designed to stabilize the unstable PAE chains via zwitterionic interactions under physiological pH (pH 7.4) and precisely program their enzyme-responsive biodegradation specifically within the intracellular compartments, ensuring targeted delivery of the cargoes. To achieve this goal, biodegradable polycaprolactone (PCL) platform is chosen, and structure-engineered several di- and triblock architectures to arrive the precise macromolecular geometry. The hydrophobic-PCL core and hydrophilic anionic-PCL block at the periphery shield PAEs against autodegradation, thereby ensuring stability under physiological pH in PBS, FBS, cell culture medium and bloodstream. The clinical anticancer drug doxorubicin and deep-tissue penetrable near-infrared IR-780 biomarker is encapsulated to study their biological actions by in vitro live cancer cells and in vivo bioimaging in live animals. These zwitterions are biocompatible, nonhemolytic, and real-time in vitro live-cell confocal studies have confirmed their internalization and enzymatic biodegradation in the endo-lysosomal compartments to deliver the payload. In vivo bioimaging establishes their prolonged blood circulation for over 72 h, and the biodistribution analysis reveals the accumulation of nanoparticles predominantly in the excretory organs., (© 2024 Wiley‐VCH GmbH.)

Polyaspartic acid derivatives are a well-known kind of polypeptide with good biocompatibility and biodegradability, and thus have been widely used as biomedical materials, including drug-loaded nano-scale micelles or macroscopic hydrogels. In this work, for the first time, monodisperse polyaspartic acid derivative microspheres with diameter ranging from 120 to 350 µm for potential tumor embolization therapy are successfully prepared by single emulsion droplet microfluidic technique. The obtained microsphere shows fast cationic anticancer drug doxorubicin hydrochloride loading kinetics with high loading capacity, which is much better than those of the commercial ones. Additionally, drug release behaviors of the drug-loaded microspheres with different diameters in different media are also studied and discussed in detail. These results provide some new insights for the preparation and potential application of polyaspartic acid derivative-based monodisperse microspheres, especially for their potential application as embolic agent., (© 2024 Wiley‐VCH GmbH.)

Therapy-induced immunogenic cell death (ICD) can initiate both innate and adaptive immune responses for amplified anti-tumor efficacy. However, dying cell-released ICD signals are prone to being sequestered by the TIM-3 receptors on dendritic cell (DC) surfaces, preventing immune surveillance. Herein, dismantlable coronated nanoparticles (NPs) are fabricated as a type of spatiotemporally controlled nanocarriers for coupling tumor cell-mediated ICD induction to DC-mediated immune sensing. These NPs are loaded with an ICD inducer, mitoxantrone (MTO), and wrapped by a redox-labile anti-TIM-3 (αTIM-3) antibody corona, forming a separable core-shell structure. The antibody corona disintegrates under high levels of extracellular reactive oxygen species in the tumor microenvironment, exposing the MTO-loaded NP core for ICD induction and releasing functional αTIM-3 molecules for DC sensitization. Systemic administration of the coronated NPs augments DC maturation, promotes cytotoxic T cell recruitment, enhances tumor susceptibility to immune checkpoint blockade, and prevents the side effects of MTO. This study develops a promising nanoplatform to unleash the potential of host immunity in cancer therapy., (© 2024 Wiley‐VCH GmbH.)

Polymeric nanoparticles (NPs) with an integrated dual delivery system enable the controlled release of bioactive molecules and drugs, providing therapeutic advantages. Key design targets include high biocompatibility, cellular uptake, and encapsulating efficiency. In this study, a polymer library derived from niacin, also known as vitamin B3 is synthesized. The library comprises poly(2-(acryloyloxy)ethyl nicotinate) (PAEN), poly(2-acrylamidoethyl nicotinate) (PAAEN), and poly(N-(2-acrylamidoethyl)nicotinamide) (PAAENA), with varying hydrophilicity in the backbone and pendant group linker. All polymers are formulated, and those with increased hydrophobicity yield NPs with homogeneous spherical distribution and diameters below 150 nm, as confirmed by scanning electron microscopy and dynamic light scattering. Encapsulation studies utilizing a model drug, neutral lipid orange (NLO), reveal the influence of polymer backbone on encapsulation efficiency. Specifically, efficiencies of 46% and 96% are observed with acrylate and acrylamide backbones, respectively. Biological investigations showed that P(AEN) and P(AAEN) NPs are non-toxic up to 300 µg mL -1 , exhibit superior cellular uptake, and boost cell metabolic activity. The latter is attributed to the cellular release of niacin, a precursor to nicotinamide adenine dinucleotide (NAD), a central coenzyme in metabolism. The results underline the potential of nutrient-derived polymers as pro-nutrient and drug-delivery materials., (© 2024 The Authors. Macromolecular Bioscience published by Wiley‐VCH GmbH.)

Due to the outbreak of novel coronavirus pneumonia, messenger RNA (mRNA) technology has attracted heated attention. A specific, safe, and efficient mRNA delivery system is needed. Lipid nanocarriers have become attractive carriers for mRNA delivery due to their high delivery efficiency, few side effects, and easy modification to change their structures and functions. To achieve the desired biological effect, lipid nanocarriers must reach the designated location for effective drug delivery. Therefore, the effects of the composition of lipid nanocarriers on their key properties are briefly reviewed. In addition, the progress of smart drug delivery by changing the composition of lipid nanocarriers is summarized, and the importance of component design and structure is emphasized. Subsequently, this review summarizes the latest progress in lipid nanocarrier-based mRNA technology and provides corresponding strategies for its current challenges, putting forward valuable information for the future design of lipid nanocarriers and mRNA., (© 2024 Wiley‐VCH GmbH.)

Nanoparticles (NPs) of noble metals such as silver (Ag NPs) or gold (Au NPs) draw the attention of scientists looking for new compounds to use in medical applications. Scientists have used metal NPs because of their easy preparation, biocompatibility, ability to influence the shape and size or modification, and surface functionalization. However, to fully use their capabilities, both the benefits and their potential threats should be considered. One possibility to reduce the potential threat and thus prevent the extinction of their properties resulting from the agglomeration, they are covered with a neutral material, thus obtaining core-shell nanostructures that can be further modified and functionalized depending on the subsequent application. In this review, we focus on discussing the properties and applications of Ag NPs and Au NPs in the medical field such as the treatment of various diseases, drug carriers, diagnostics, and many others. In addition, the following review also discusses the use and potential applications of Ag@SiO 2 and Au@SiO 2 core-shell nanostructures, which can be used in cancer therapy and diagnosis, treatment of infections, or tissue engineering., (© 2024 Wiley-VCH GmbH.)

Apohemoprotein is focused on the field of theranostics, serving as a porphyrin carrier. Hemoglobin (Hb) consists of α 2 β 2 tetramer with iron(II)-protoporphyrin IX (heme) bound to each globin. However, heme-removed Hb (apoHb) causes dissociation at αβ interfaces and aggregation under physiological conditions. We synthesized a stable apoHb derivative comprising intramolecular-crosslinked apoHb (apoXHb) and human serum albumin (HSA), apoXHb-HSA 3 . ApoXHb-HSA 3 engendered no aggregates in the physiological solutions. Moreover, apoXHb-HSA 3 was reconstituted with zinc(II)-protoporphyrin IX (ZnP), generating ZnXHb-HSA 3 , a potent photosensitizer for photodynamic therapy (PDT). The photophysical properties of ZnXHb-HSA 3 were identical to those of zinc-substituted XHb (ZnXHb). Cellular uptake behavior was evaluated using various cancer cell lines. ZnXHb-HSA 3 released ZnP around the cells, and the free ZnP penetrated cell membranes. In contrast, protein units were not observed within the cells. ZnXHb-HSA 3 showed no cytotoxicity under dark conditions and demonstrated superior PDT activity in comparison to naked ZnXHb. ZnXHb-HSA 3 acts as an innovative porphyrin carrier for enhanced PDT., (© 2024 Wiley-VCH GmbH.)

Age-related macular degeneration (AMD) disease has become a worldwide senile disease, and frequent intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) is the mainstream treatment in the clinic, which is associated with sight-threatening complications. Herein, nintedanib, an inhibitor of angiogenesis, and lutein, a potent antioxidant, can co-assemble into nanoparticles through multiple noncovalent interactions. Interestingly, the co-assembled lutein/nintedanib nanoparticles (L/N NPs) exhibit significantly improved stability and achieve long-term sustained release of two drugs for at least two months in mice. Interestingly, in rabbit eyeball with a more complete barrier system, the L/N NPs still successfully distribute in the retina and choroid for a month. In the laser-induced mouse choroidal neovascularization model, the L/N NPs after a minimally invasive subconjunctival administration can successfully inhibit angiogenesis and achieve comparable and even better therapeutic results to that of standard intravitreal injection of anti-VEGF. Therefore, the subconjunctival injection of L/N NPs with long-term sustained drug release behavior represents a promising and innovative strategy for AMD treatment. Such minimally invasive administration together with the ability to effectively inhibit angiogenesis reduce inflammation and counteract oxidative stress and holds great potential for improving patient outcomes and quality of life in those suffering from this debilitating eye condition., (© 2024 Wiley‐VCH GmbH.)

The quest for effective and reliable methods of delivering medications, with the aim of improving delivery of therapeutic agent to the intended location, has presented a demanding yet captivating field in biomedical research. The concept of smart drug delivery systems is an evolving therapeutic approach, serving as a model for directing drugs to specific targets or sites. These systems have been developed to specifically target and regulate the administration of therapeutic substances in a diverse array of chronic conditions, including periodontitis, diabetes, cardiac diseases, inflammatory bowel diseases, rheumatoid arthritis, and different cancers. Nevertheless, numerous comprehensive clinical trials are still required to ascertain both the immediate and enduring impacts of such nanosystems on human subjects. This review delves into the benefits of different drug delivery vehicles, aiming to enhance comprehension of their applicability in addressing present medical requirements. Additionally, it touches upon the current applications of these stimuli-reactive nanosystems in biomedicine and outlines future development prospects., (© 2024 Wiley‐VCH GmbH.)

Combining immune checkpoint blockade with chemotherapy through nanotechnology is promising in terms of safety and efficacy. However, the distinct subcellular distribution of each ingredient's action site makes it challenging to acquire an optimal synergism. Herein, a dual-pH responsive hybrid polymeric micelle system, HNP(αPDL1 6.9 , Dox 5.3 ), is constructed as a proof-of-concept for the spatial cooperativity in chemo-immunotherapy. HNP retains the inherent pH-transition of each polymer, with stepwise disassembly under discrete pH thresholds. Within weakly acidic extracellular tumor environment, αPDL1 is first released to block the checkpoint on cell membranes. The remaining intact Doxorubicin-loaded micelle NP(Dox) 5.3 displays significant tropism toward tumor cells and releases Dox upon lysosomal pH for efficient tumor immunogenic cell death without immune toxicity. This sequential-released pattern boosts DC activation and primes CD8 + T cells, leading to enhanced therapeutic performance than single agent or an inverse-ordered combination in multiple murine tumor models. Using HNP, the indispensable role of conventional type 1 DC (cDC1) is identified in chemo-immunotherapy. A co-signature of cDC1 and CD8 correlates with cancer patient survival after neoadjuvant Pembrolizumab plus chemotherapy in clinic. This study highlights spatial cooperativity of chemo- and immuno-agents in immunoregulation and provides insights into the rational design of drug combination for future nanotherapeutics development., (© 2024 Wiley‐VCH GmbH.)