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Abstract HIF‐1α (hypoxia induced factor‐1α), a vital protective signal against hypoxia, has a short lifetime after myocardial infarction (MI). Increasing HIF‐1α stability by inhibiting its hydroxylation with prolyl hydroxylases inhibitors such as DPCA (1,4‐dihydrophenonthrolin‐4‐one‐3‐carboxylic acid) presents positive results. However, the optimal inhibitor administration profile for MI treatment is still unexplored. Here, injectable, thermosensitive hydrogels with programmable DPCA release are designed and synthesized. Hydrogel degradation and slow DPCA release are coupled to form a feedback loop by attaching pendant DPCA to polymer backbone, which serve as additional crosslinking points through π–π and hydrophobic interactions. Pendant carboxyl groups are added to the copolymer to accelerate DPCA release. Burst release in the acute phase for myocardial protection and extended near zero‐order release across the inflammatory and fibrotic phases with different rates are achieved. All DPCA‐releasing hydrogels upregulate HIF‐1α, decrease apoptosis, promote angiogenesis, and stimulate cardiomyocyte proliferation, leading to preserved cardiac function and ventricular geometry. Faster hydrogel degradation induced by faster DPCA release results in a HIF‐1α expression eight times of healthy control and better therapeutic effect in MI treatment. This research demonstrates the value of precise regulation of HIF‐1α expression in treating MI and other relevant diseases and provides an implantable device‐based modulation strategy.

Abstract Myocardial ischemia/reperfusion injury (MI/RI) generates reactive oxygen species (ROS) and initiates inflammatory responses. Traditional therapies targeting specific cytokines or ROS often prove inadequate. An innovative drug delivery system (DDS) is developed using neutrophil decoys (NDs) that encapsulate 18β‐glycyrrhetinic acid (GA) within a hydrolyzable oxalate polymer (HOP) and neutrophil membrane vesicles (NMVs). These NDs are responsive to hydrogen peroxide (H2O2), enabling controlled GA release. Additionally, NDs adsorb inflammatory factors, thereby reducing inflammation. They exhibit enhanced adhesion to inflamed endothelial cells (ECs) and improved penetration. Once internalized by cardiomyocytes through clathrin‐mediated endocytosis, NDs protect against ROS‐induced damage and inhibit HMGB1 translocation. In vivo studies show that NDs preferentially accumulate in injured myocardium, reducing infarct size, mitigating adverse remodeling, and enhancing cardiac function, all while maintaining favorable biosafety profiles. This neutrophil‐based system offers a promising targeted therapy for MI/RI by addressing both inflammation and ROS, holding potential for future clinical applications.

Abstract Messenger RNA (mRNA) has emerged as an attractive therapeutic molecule for a plethora of clinical applications. For in vivo functionality, mRNA therapeutics require encapsulation into effective, stable, and safe delivery systems to protect the cargo from degradation and reduce immunogenicity. Here, a bioengineering platform for efficient mRNA loading and functional delivery using bionormal nanoparticles, extracellular vesicles (EVs), is established by expressing a highly specific RNA‐binding domain fused to CD63 in EV producer cells stably expressing the target mRNA. The additional combination with a fusogenic endosomal escape moiety, Vesicular Stomatitis Virus Glycoprotein, enables functional mRNA delivery in vivo at doses substantially lower than currently used clinically with synthetic lipid‐based nanoparticles. Importantly, the application of EVs loaded with effective cancer immunotherapy proves highly effective in an aggressive melanoma mouse model. This technology addresses substantial drawbacks currently associated with EV‐based nucleic acid delivery systems and is a leap forward to clinical EV applications.

Abstract Peptide coacervates self‐assembling via liquid‐liquid phase separation are appealing intracellular delivery vehicles of macromolecular therapeutics (proteins, DNA, mRNA) owing to their non‐cytotoxicity, high encapsulation capacity, and efficient cellular uptake. However, the mechanisms by which these viscoelastic droplets cross the cellular membranes remain unknown. Here, using multimodal imaging, data analytics, and biochemical inhibition assays, we identify the key steps by which droplets enter the cell. We find that the uptake follows a non‐canonical pathway and instead integrates essential features of macropinocytosis and phagocytosis, namely active remodeling of the actin cytoskeleton and appearance of filopodia‐like protrusions. Experiments using giant unilamellar vesicles show that the coacervates attach to the bounding membrane in a charge‐ and cholesterol‐dependent manner but do not breach the lipid bilayer barrier. Cell uptake in the presence of small molecule inhibitors – interfering with actin and tubulin polymerization – confirm the active role of cytoskeleton remodeling, most prominently evident in electron microscopy imaging. These findings suggest a peculiar internalization mechanism for viscoelastic, glassy coacervate droplets combining features of non‐specific uptake of fluids by macropinocytosis and particulate uptake of phagocytosis. The broad implications of this study will enable to enhance the efficacy and utility of coacervate‐based strategies for intracellular delivery of macromolecular therapeutics.

Abstract Hydrogels have been used in the clinic since the late 1980s with broad applications in drug delivery, cosmetics, tissue regeneration, among many other areas. The past three decades have witnessed rapid advances in the fields of polymer chemistry, crosslinking approaches, and hydrogel fabrication methods, which have collectively brought many new hydrogel products, either injectable or non‐injectable, to clinical studies. In an article published in 2020 entitled “Hydrogels in the clinic”, we reviewed the clinical landscape and translational challenges of injectable hydrogels. Here, we provide an update on the advances in the field and also extend the scope to include non‐injectable hydrogels. We highlight recently approved hydrogel products, provide an update on the clinical trials of injectable hydrogels, and discuss active clinical trials of topically applied and implantable hydrogels.

Abstract Conventional chemotherapeutic agents are limited by their lack of targeting and penetration and their short retention time, and chemotherapy might induce an immune suppressive environment. Peptide self‐assembly can result in a specific morphology, and the resulting morphological changes are stimuli responsive to the external environment, which is important for drug permeation and retention of encapsulated chemotherapeutic agents. In this study, a polypeptide (Pep1) containing the peptide sequences PLGLAG and RGD that is responsive to matrix metalloproteinase 2 (MMP‐2) was successfully developed. Pep1 underwent a morphological transformation from a spherical structure to aggregates with a high aspect ratio in response to MMP‐2 induction. This drug delivery system (DI/Pep1) can transport doxorubicin (DOX) and indomethacin (IND) simultaneously to target tumor cells for subsequent drug release while extending drug retention within tumor cells, which increases immunogenic cell death and facilitates the immunotherapeutic effect of CD4+ T cells. Ultimately, DI/Pep1 attenuated tumor‐associated inflammation, enhanced the body's immune response, and inhibited breast cancer growth by combining the actions of DOX and IND. Our research offers an approach to hopefully enhance the effectiveness of cancer treatment.

Abstract Liver fibrosis, arising from factors such as viral infections or metabolic disorders, represents an ongoing global health challenge and is a major risk factor for hepatocellular carcinoma. Unfortunately, there are no clinically approved drugs available for its treatment. Recent studies have illuminated the pivotal role of macrophage recruitment in the pathogenesis of liver fibrosis, presenting a potential therapeutic target. Therefore, it holds great promise to develop novel anti‐fibrotic therapies capable of inhibiting this process. Herein, a drug‐loaded biomimetic nanodecoy (CNV‐C) is developed by harnessing genetically engineered cellular vesicles for the treatment of liver fibrosis. CNV‐C is equipped with a C‐C motif chemokine receptor 2 (CCR2)‐overexpressed surface, enabling it to selectively neutralize elevated levels of C‐C motif chemokine ligand 2 (CCL2), thereby reducing macrophage infiltration and the subsequent production of the fibrogenic cytokine transforming growth factor β (TGF‐β). Moreover, curcumin, an anti‐fibrotic agent, is loaded into CNV‐C and delivered to the liver, facilitating its efficacy in suppressing the activation of hepatic stellate cells by blocking the downstream TGF‐β/Smad signaling. This combinational therapy ultimately culminates in the alleviation of liver fibrosis in a mouse model induced by carbon tetrachloride. Collectively, the findings provide groundbreaking proof‐of‐concept for employing genetically modified nanodecoys to manage liver fibrosis, which may usher in a new era of anti‐fibrotic treatments.

Abstract Microbubbles (MB) are widely used as contrast agents for ultrasound (US) imaging and US‐enhanced drug delivery. Polymeric MB are highly suitable for these applications because of their acoustic responsiveness, high drug loading capability, and ease of surface functionalization. While many studies have focused on using polymeric MB for diagnostic and therapeutic purposes, relatively little attention has thus far been paid to improving their inherent imaging and drug delivery features. This study here shows that manipulating the polymer chemistry of poly(butyl cyanoacrylate) (PBCA) MB via temporarily mixing the monomer with the monomer‐mimetic butyl cyanoacetate (BCC) during the polymerization process improves the drug loading capacity of PBCA MB by more than twofold, and the in vitro and in vivo acoustic responses of PBCA MB by more than tenfold. Computer simulations and physisorption experiments show that BCC manipulates the growth of PBCA polymer chains and creates nanocavities in the MB shell, endowing PBCA MB with greater drug entrapment capability and stronger acoustic properties. Notably, because BCC can be readily and completely removed during MB purification, the resulting formulation does not include any residual reagent beyond the ones already present in current PBCA‐based MB products, facilitating the potential translation of next‐generation PBCA MB.

Abstract Recently, the field of nanomedicine has witnessed substantial advancements in the development of nanocarriers for targeted drug delivery, emerges as promising platforms to enhance therapeutic efficacy and minimize adverse effects associated with conventional chemotherapy. Notably, deformable nanocarriers have garnered considerable attention due to their unique capabilities of size changeable, tumor‐specific aggregation, stimuli‐triggered disintegration, and morphological transformations. These deformable nanocarriers present significant opportunities for revolutionizing drug delivery strategies, by responding to specific stimuli or environmental cues, enabling achieved various functions at the tumor site, including size‐shrinkage nanocarriers enhance drug penetration, aggregative nanocarriers enhance retention effect, disintegrating nanocarriers enable controlled drug release, and shape‐changing nanocarriers improve cellular uptake, allowing for personalized treatment approaches and combination therapies. This review provides an overview of recent developments and applications of deformable nanocarriers for enhancing tumor therapy, underscores the diverse design strategies employed to create deformable nanocarriers and elucidates their remarkable potential in targeted tumor therapy.

Abstract Inflammatory bowel disease (IBD) is a recurring chronic inflammatory disease. Current treatment strategies are aimed at alleviating clinical symptoms and are associated with gastrointestinal or systemic adverse effects. New delivery strategies are needed for the treatment of IBD. Bacteria are promising biocarriers, which can produce drugs in situ and sense the gut in real time. Herein, we focus on recent studies of engineered bacteria used for IBD treatment and introduce the application of engineered bacteria in the diagnosis. On this basis, the current dilemmas and future developments of bacterial delivery systems are discussed.

Abstract The prevention of blindness from glaucoma requires multiple treatments to lower intraocular pressure. Here, human contact lenses are modified with highly porous metal‐organic frameworks with sustained release of brimonidine for prolonged glaucoma treatment. Various metal‐organic frameworks were screened for their attachment to lenses, loading with brimonidine, and drug‐release properties. Optimized therapeutic ocular lenses conjugated with MIL‐101(Cr) frameworks maintain optical transparency and power. Coating of lenses with MIL‐101(Cr) nanoparticles reduced brimonidine washout with tears and ensured a gradual and localized release of the drug into the eyeball through the cornea. The hybrid lenses provided a 4.5‐fold better decrease in eye pressure, compared by area under the curve (AUC) value to a commercially available brimonidine tartrate solution. Therapeutic lenses did not induce any notable eye irritation or corneal damage in vivo. The newly developed hybrid lenses are expected to provide a robust platform for the therapy and prevention of various ocular diseases.

Abstract Hydrogels are extensively employed in healthcare due to their adaptable structures, high water content, and biocompatibility, with FDA‐approved applications ranging from spinal cord regeneration to local therapeutic delivery. However, clinical hydrogels encounter challenges related to inconsistent therapeutic exposure, unmodifiable release windows, and difficulties in subsurface polymer insertion. Addressing these issues, we engineered injectable, biocompatible hydrogels as a local therapeutic depot, utilizing poly(ethylene glycol) (PEG)‐based hydrogels functionalized with bioorthogonal SPAAC handles for network polymerization and functionalization. Our hydrogel solutions polymerize in situ in a temperature‐sensitive manner, persist in tissue, and facilitate the delivery of bioactive therapeutics in subsurface locations. Demonstrating the efficacy of our approach, recombinant anti‐CD47 monoclonal antibodies, when incorporated into subsurface‐injected hydrogel solutions, exhibited cytotoxic activity against infiltrative high‐grade glioma xenografts in the rodent brain. To enhance the gel's versatility, recombinant protein cargos can undergo site‐specific modification with hydrolysable “azidoester” adapters, allowing for user‐defined release profiles from the hydrogel. Hydrogel‐generated gradients of murine CXCL10, linked to intratumorally injected hydrogel solutions via azidoester linkers, resulted in significant recruitment of CD8+ T‐cells and the attenuation of tumor growth in a “cold” syngeneic melanoma model. This study highlights a highly customizable, hydrogel‐based delivery system for local protein therapeutic administration to meet diverse clinical needs.

Abstract The extracellular matrix (ECM) is critical for drug resistance in colorectal cancer (CRC). The abundant collagen within the ECM significantly influences tumor progression and matrix‐mediated drug resistance (MMDR) by binding to discoidin domain receptor 1 (DDR1), but the specific mechanisms by which tumor cells modulate ECM via DDR1 and ultimately regulate TME remain poorly understand. Furthermore, overcoming drug resistance by modulating the tumor ECM remains a challenge in CRC treatment. In this study, a novel mechanism is elucidated by which DDR1 mediates the interactions between tumor cells and collagen, enhances collagen barriers, inhibits immune infiltration, promotes drug efflux, and leads to MMDR in CRC. To address this issue, a multistage drug delivery system carrying DDR1‐siRNA and chemotherapeutic agents is employed to disrupt collagen barriers by silencing DDR1 in tumor, enhancing chemotherapy drugs diffusion and facilitating immune infiltration. These findings not only revealed a novel role for collagen‐rich matrix mediated by DDR1 in tumor resistance, but also introduced a promising CRC treatment strategy.

Abstract Small‐scale robots offer significant potential in minimally invasive medical procedures. Due to the nature of soft biological tissues, however, robots are exposed to complex environments with various challenges in locomotion, which is essential to overcome for useful medical tasks. A single mini‐robot often provides insufficient force on slippery biological surfaces to carry medical instruments, such as a fluid catheter or an electrical wire. Here, for the first time, a team of millirobots (TrainBot) is reported to generate around two times higher actuating force than a TrainBot unit by forming a convoy to collaboratively carry long and heavy cargos. The feet of each unit are optimized to increase the propulsive force around three times so that it can effectively crawl on slippery biological surfaces. A human‐scale permanent magnetic set‐up is developed to wirelessly actuate and control the TrainBot to transport heavy and lengthy loads through narrow biological lumens, such as the intestine and the bile duct. The first electrocauterization performed by the TrainBot is demonstrated to relieve a biliary obstruction and open a tunnel for fluid drainage and drug delivery. The developed technology sheds light on the collaborative strategy of small‐scale robots for future minimally invasive surgical procedures.

Abstract Periodontitis, a prevalent chronic inflammatory disease, poses significant challenges for effective treatment due to its complex etiology involving specific bacteria and the inflammatory immune microenvironment. Here, this study presents a novel approach for the targeted treatment of periodontitis utilizing the immunomodulatory and antibacterial properties of Embelin, a plant‐derived compound, within an injectable hydrogel system. The developed Carboxymethyl Chitosan‐Oxidized Dextran (CMCS‐OD) hydrogel formed via dynamic chemical bonds exhibited self‐healing capabilities and pH‐responsive behavior, thereby facilitating the controlled release of Embelin and enhancing its efficacy in a dynamic oral periodontitis microenvironment. This study demonstrates that this hydrogel system effectively prevents bacterial invasion and mitigates excessive immune response activation. Moreover, it precisely modulates macrophage M1/M2 phenotypes and suppresses inflammatory cytokine expression, thereby fostering a conducive environment for bone regeneration and addressing periodontitis‐induced bone loss. These findings highlight the potential of the approach as a promising strategy for the clinical management of periodontitis‐induced bone destruction.

Abstract Photonic crystals are a new class of optical microstructure materials characterized by a dielectric constant that varies periodically with space and features a photonic bandgap. Inspired by natural photonic crystals such as butterfly scales, a series of artificial photonic crystals are developed for use in integrated photonic platforms, biosensing, communication, and other fields. Among them, colloidal photonic crystals (CPCs) have gained widespread attention due to their excellent optical properties and advantages, such as ease of preparation and functionalization. This work reviews the classification and self‐assembly principles of CPCs, details some of the latest biomedical applications of large‐area, high‐quality CPCs prepared using advanced self‐assembly methods, summarizes the existing challenges in CPC construction and application, and anticipates future development directions and optimization strategy. With further advancements, CPCs are expected to play a more critical role in biosensors, drug delivery, cell research, and other fields, bringing significant benefits to biomedical research and clinical practice.

Abstract Funduscopic diseases, including diabetic retinopathy (DR) and age‐related macular degeneration (AMD), significantly impact global visual health, leading to impaired vision and irreversible blindness. Delivering drugs to the posterior segment of the eye remains a challenge due to the presence of multiple physiological and anatomical barriers. Conventional drug delivery methods often prove ineffective and may cause side effects. Nanomaterials, characterized by their small size, large surface area, tunable properties, and biocompatibility, enhance the permeability, stability, and targeting of drugs. Ocular nanomaterials encompass a wide range, including lipid nanomaterials, polymer nanomaterials, metal nanomaterials, carbon nanomaterials, quantum dot nanomaterials, and so on. These innovative materials, often combined with hydrogels and exosomes, are engineered to address multiple mechanisms, including macrophage polarization, reactive oxygen species (ROS) scavenging, and anti‐vascular endothelial growth factor (VEGF). Compared to conventional modalities, nanomedicines achieve regulated and sustained delivery, reduced administration frequency, prolonged drug action, and minimized side effects. This study delves into the obstacles encountered in drug delivery to the posterior segment and highlights the progress facilitated by nanomedicine. Prospectively, these findings pave the way for next‐generation ocular drug delivery systems and deeper clinical research, aiming to refine treatments, alleviate the burden on patients, and ultimately improve visual health globally.

Abstract The activation of cyclic GMP‐AMP (cGAMP) synthase (cGAS) and its adaptor, stimulator of interferon genes (STING), is known to reprogram the immunosuppressive tumor microenvironment for promoting antitumor immunity. To enhance the efficiency of cGAS‐STING pathway activation, macrophage‐selective uptake, and programmable cytosolic release are crucial for the delivery of STING agonists. However, existing polymer‐ or lipid‐based delivery systems encounter difficulty in integrating multiple functions meanwhile maintaining precise control and simple procedures. Herein, inspired by cGAS being a natural DNA sensor, a modularized DNA nanodevice agonist (DNDA) is designed that enable macrophage‐selective uptake and programmable activation of the cGAS‐STING pathway through precise self‐assembly. The resulting DNA nanodevice acts as both a nanocarrier and agonist. Upon local administration, it demonstrates the ability of macrophage‐selective uptake, endosomal escape, and cytosolic release of the cGAS‐recognizing DNA segment, leading to robust activation of the cGAS‐STING pathway and enhanced antitumor efficacy. Moreover, DNDA elicits a synergistic therapeutic effect when combined with immune checkpoint blockade. The study broadens the application of DNA nanotechnology as an immune stimulator for cGAS‐STING activation.

Abstract Since extracellular vesicles (EVs) have emerged as a promising drug delivery system, diverse methods have been used to load them with active pharmaceutical ingredients (API) in preclinical and clinical studies. However, there is yet to be an engineered EV formulation approved for human use, a barrier driven in part by the intrinsic heterogeneity of EVs. API loading is rarely assessed in the context of single vesicle measurements of physicochemical properties but is likely administered in a heterogeneous fashion to the detriment of a consistent product. Here, we applied a suite of single‐particle resolution methods to determine the loading of rhodamine 6G (R6G) surrogate cargo mimicking hydrophilic small molecule drugs across four common API loading methods: sonication, electroporation, freeze‐thaw cycling and passive incubation. Loading efficiencies and alterations in the physical properties of EVs were assessed, as well as co‐localization with common EV‐associated tetraspanins (i.e., CD63, CD81 and CD9) for insight into EV subpopulations. Sonication had the highest loading efficiency, yet significantly decreased particle yield, while electroporation led to the greatest number of loaded API particles, albeit at a lower efficiency. Moreover, results were often inconsistent between repeated runs within a given method, demonstrating the difficulty in developing a rigorous loading method that consistently loaded EVs across their heterogeneous subpopulations. This work highlights the significance of how chosen quantification metrics can impact apparent conclusions and the importance of single‐particle characterization of EV loading.

Abstract Exosomes are signalling molecules related to cell‐to‐cell communication. Based on sources (plants, stem cells, and immune cells derived exosomes) it offers promising therapeutic activity against cancer. Plant‐derived exosomes (PDEs) are natural extracellular vesicles (EVs) that are potent to provide organic precision nanomedicine to cancer therapeutics including targeted drug delivery. PDEs are gaining attention due to their safety and efficacy. There are plenty of different sources of PDEs in nature. This article explores various plants such as carrots, ginger, lemons, cabbages, blueberries, oranges, tomatoes, grapefruits, and tea leaves, which provide exosomes with distinct therapeutic properties, including anti‐inflammatory, antioxidant, and anticancer activities. PDEs exhibit significant potential in drug delivery. Ongoing research and clinical trials predict that PDEs will become effective, and affordable solutions for cancer treatment.

Abstract Considerable progress has been made in the development of drug delivery systems for diabetic wounds. However, underlying drawbacks, such as low delivery efficiency and poor tissue permeability, have rarely been addressed. In this study, a multifunctional biohybrid nanorobot platform comprising an artificial unit and several biological components is constructed. The artificial unit is a magnetically driven nanorobot surface modified with antibacterial 2‐hydroxypropyltrimethyl ammonium chloride chitosan, which enables the entire platform to move and has excellent tissue penetration capacity. The biological components are two‐step engineered extracellular vesicles that are first loaded with mangiferin, a natural polyphenolic compound with antioxidant properties, and then glycoengineered on the surface to enhance cellular uptake efficiency. As expected, the platform is more easily absorbed by endothelial cells and fibroblasts and exhibits outstanding dermal penetration performance and antioxidant properties. Encouraging results are also observed in infected diabetic wound models, showing improved wound re‐epithelialization, collagen deposition, angiogenesis, and accelerated wound healing. Collectively, a biohybrid nanorobot platform that possesses the functionalities of both artificial units and biological components serves as an efficient delivery system to promote diabetic wound repair through dual‐enhanced cell and tissue penetration and multistep interventions.

Abstract Nanomaterials have aroused great interests in drug delivery due to their nanoscale structure, facile modifiability, and multifunctional physicochemical properties. Currently, stimuli‐responsive nanomaterials that can respond to endogenous or exogenous stimulus display strong potentials in biomedical applications. In comparison with conventional nanomaterials, stimuli‐responsive nanomaterials can improve therapeutic efficiency and reduce the toxicity of drugs toward normal tissues through specific targeting and on‐demand drug release at pathological sites. In this review, we summarize the responsive mechanism of a variety of stimulus, including pH, redox, and enzymes within pathological microenvironment, as well as exogenous stimulus such as thermal effect, magnetic field, light, and ultrasound. After that, biomedical applications (e.g., drug delivery, imaging, and theranostics) of stimuli‐responsive nanomaterials in a diverse array of common diseases, including cardiovascular diseases, cancer, neurological disorders, inflammation, and bacterial infection, are presented and discussed. Finally, the remaining challenges and outlooks of future research directions for the biomedical applications of stimuli‐responsive nanomaterials are also discussed. We hope that this review can provide valuable guidance for developing stimuli‐responsive nanomaterials and accelerate their biomedical applications in diseases diagnosis and treatment.

Abstract Exosomes are nanoscale vesicles of cellular origin. One of the main characteristics of exosomes is their ability to carry a wide range of biomolecules from their parental cells, which are important mediators of intercellular communication and play an important role in physiological and pathological processes. Exosomes have the advantages of biocompatibility, low immunogenicity, and wide biodistribution. As researchers’ understanding of exosomes has increased, various strategies have been proposed for their use in diagnosing and treating diseases. Here, we provide an overview of the biogenesis and composition of exosomes, describe the relationship between exosomes and disease progression, and focus on the use of exosomes as biomarkers for early screening, disease monitoring, and guiding therapy in refractory diseases such as tumors and neurodegenerative diseases. We also summarize the current applications of exosomes, especially engineered exosomes, for efficient drug delivery, targeted therapies, gene therapies, and immune vaccines. Finally, the current challenges and potential research directions for the clinical application of exosomes are also discussed. In conclusion, exosomes, as an emerging molecule that can be used in the diagnosis and treatment of diseases, combined with multidisciplinary innovative solutions, will play an important role in clinical applications.

Abstract Mesenchymal stem cells (MSCs) are recruited by malignant tumor cells to the tumor microenvironment (TME) and play a crucial role in the initiation and progression of malignant tumors. This role encompasses immune evasion, promotion of angiogenesis, stimulation of cancer cell proliferation, correlation with cancer stem cells, multilineage differentiation within the TME, and development of treatment resistance. Simultaneously, extensive research is exploring the homing effect of MSCs and MSC‐derived extracellular vesicles (MSCs‐EVs) in tumors, aiming to design them as carriers for antitumor substances. These substances are targeted to deliver antitumor drugs to enhance drug efficacy while reducing drug toxicity. This paper provides a review of the supportive role of MSCs in tumor progression and the associated molecular mechanisms. Additionally, we summarize the latest therapeutic strategies involving engineered MSCs and MSCs‐EVs in cancer treatment, including their utilization as carriers for gene therapeutic agents, chemotherapeutics, and oncolytic viruses. We also discuss the distribution and clearance of MSCs and MSCs‐EVs upon entry into the body to elucidate the potential of targeted therapies based on MSCs and MSCs‐EVs in cancer treatment, along with the challenges they face.

Abstract 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.

Abstract Esophageal squamous cell carcinoma (ESCC) is a prevalent gastrointestinal cancer characterized by high mortality and an unfavorable prognosis. While combination therapies involving surgery, chemotherapy, and radiation therapy are advancing, targeted therapy for ESCC remains underdeveloped. As a result, the overall five‐year survival rate for ESCC is still below 20%. Herein, ESCC‐specific DNA aptamers and an innovative aptamer‐modified nano‐system is introduced for targeted drug and gene delivery to effectively inhibit ESCC. The EA1 ssDNA aptamer, which binds robustly to ESCC cells with high specificity and affinity, is identified using cell‐based systematic evolution of ligands by exponential enrichment (cell‐SELEX). An EA1‐modified nano‐system is developed using a natural egg yolk lipid nanovector (EA1‐EYLNs‐PTX/siEFNA1) that concurrently loads paclitaxel (PTX) and a small interfering RNA of Ephrin A1 (EFNA1). This combination counters ESCC's proliferation, migration, invasion, and lung metastasis. Notably, EFNA1 is overexpressed in ESCC tumors with lung metastasis and has an inverse correlation with ESCC patient prognosis. The EA1‐EYLNs‐PTX/siEFNA1 nano‐system offers effective drug delivery and tumor targeting, resulting in significantly improved therapeutic efficacy against ESCC tumors. These insights suggest that aptamer‐modified nano‐systems can deliver drugs and genes with superior tumor‐targeting, potentially revolutionizing targeted therapy in ESCC.

Abstract Soluble angiotensin‐converting enzyme 2 (ACE2) can act as a decoy molecule that neutralizes severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) by blocking spike (S) proteins on virions from binding ACE2 on host cells. Based on structural insights of ACE2 and S proteins, we designed a “muco‐trapping” ACE2‐Fc conjugate, termed ACE2‐(G4S)6‐Fc, comprised of the extracellular segment of ACE2 (lacking the C‐terminal collectrin domain) that is linked to mucin‐binding IgG1‐Fc via an extended glycine‐serine flexible linker. ACE2‐(G4S)6‐Fc exhibits substantially greater binding affinity and neutralization potency than conventional full length ACE2‐Fc decoys or similar truncated ACE2‐Fc decoys without flexible linkers, possessing picomolar binding affinity and strong neutralization potency against pseudovirus and live virus. ACE2‐(G4S)6‐Fc effectively trapped fluorescent SARS‐CoV‐2 virus like particles in fresh human airway mucus and was stably nebulized using a commercial vibrating mesh nebulizer. Intranasal dosing of ACE2‐(G4S)6‐Fc in hamsters as late as 2 days postinfection provided a 10‐fold reduction in viral load in the nasal turbinate tissues by Day 4. These results strongly support further development of ACE2‐(G4S)6‐Fc as an inhaled immunotherapy for COVID‐19, as well as other emerging viruses that bind ACE2 for cellular entry.

Abstract Drug‐carrying nanoparticles are a promising strategy to deliver therapeutics into the brain, but their translation requires better characterization of interactions between nanomaterials and endothelial cells of the blood–brain barrier (BBB). Here, we use a library of 18 layer‐by‐layer electrostatically assembled nanoparticles (NPs) to independently assess the impact of NP core and surface materials on in vitro uptake, transport, and intracellular trafficking in brain endothelial cells. We demonstrate that NP core stiffness determines the magnitude of transport, while surface chemistry directs intracellular trafficking. Finally, we demonstrate that these factors similarly dictate in vivo BBB transport using intravital imaging through cranial windows in mice. We identify that hyaluronic acid surface chemistry increases transport across the BBB in vivo, and flow conditions are necessary to replicate this finding in vitro. Taken together, these findings highlight the importance of assay geometry, cell biology, and fluid flow in developing nanocarriers for delivery to the brain.

Abstract Traumatic brain injury (TBI) can have long‐lasting physical, emotional, and cognitive consequences due to the neurodegeneration caused by its robust inflammatory response. Despite advances in rehabilitation care, effective neuroprotective treatments for TBI patients are lacking. Furthermore, current drug delivery methods for TBI treatment are inefficient in targeting inflamed brain areas. To address this issue, we have developed a liposomal nanocarrier (Lipo) encapsulating dexamethasone (Dex), an agonist for the glucocorticoid receptor utilized to alleviate inflammation and swelling in various conditions. In vitro studies show that Lipo‐Dex were well tolerated in human and murine neural cells. Lipo‐Dex showed significant suppression of inflammatory cytokines, IL‐6 and TNF‐α, release after induction of neural inflammation with lipopolysaccharide. Further, the Lipo‐Dex were administered to young adult male and female C57BL/6 mice immediately after controlled cortical impact injury (a TBI model). Our findings demonstrate that Lipo‐Dex can selectively target the injured brain, thereby reducing lesion volume, cell death, astrogliosis, the release of pro‐inflammatory cytokines, and microglial activation compared to Lipo‐treated mice in a sex‐dependent manner, showing a major impact only in male mice. This highlights the importance of considering sex as a crucial variable in developing and evaluating new nano‐therapies for brain injury. These results suggest that Lipo‐Dex administration may effectively treat acute TBI.

Abstract Peripheral nerve block is performed for precise pain control and lesser side effects after surgery by reducing opioid consumption. Injectable hydrogel delivery systems with high biosafety and moisture content have good clinical application prospects for local anesthetic delivery. However, how to achieve high drug loading and long‐term controlled release of water‐soluble narcotic drugs remains a big challenge. In this study, heterogeneous microspheres and an injectable gel‐matrix composite drug delivery system are designed in two steps. First, heterogeneous hydrogel microspheres loaded with ropivacaine (HMS‐ROP) are prepared using a microfluidic chip and in situ alkalization. An injectable self‐healing hydrogel matrix (Gel) is then prepared from modified carboxymethylcellulose (CMC‐ADH) and oxidized hyaluronic acid (OHA). A local anesthetic delivery system, Gel/HMS‐ROP/dexmedetomidine (DEX), with long‐term retention and drug release in vivo is prepared by combining HMS‐ROP and Gel/DEX. The drug loading of HMS‐ROP reached 41.1%, with a drug release time of over 160 h in vitro, and sensory and motor blockade times in vivo of 48 and 36 h, respectively. In summary, the sequential release and synergistic analgesic effects of the two anesthetics are realized using core‐shell microspheres, DEX, and an injectable gel, providing a promising strategy for long‐acting postoperative pain management.

Abstract Intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) is the primary treatment for ischemic stroke. However, rtPA treatment can substantially increase blood‐brain barrier (BBB) permeability and susceptibility to hemorrhagic transformation. Herein, the mechanism underlying the side effects of rtPA treatment is investigated and demonstrated that ferroptosis plays an important role. The ferroptosis inhibitor, liproxstatin‐1 (Lip) is proposed to alleviate the side effects. A well‐designed macrocyclic carrier, glucose‐modified azocalix[4]arene (GluAC4A), is prepared to deliver Lip to the ischemic site. GluAC4A bound tightly to Lip and markedly improved its solubility. Glucose, modified at the upper rim of GluAC4A, imparts BBB targeting to the drug delivery system owing to the presence of glucose transporter 1 on the BBB surface. The responsiveness of GluAC4A to hypoxia due to the presence of azo groups enabled the targeted release of Lip at the ischemic site. GluAC4A successfully improved drug accumulation in the brain, and Lip@GluAC4A significantly reduced ferroptosis, BBB leakage, and neurological deficits induced by rtPA in vivo. These findings deepen the understanding of the side effects of rtPA treatment and provide a novel strategy for their effective mitigation, which is of great significance for the treatment and prognosis of patients with ischemic stroke.

Abstract Atherosclerosis, a chronic disease associated with metabolism, poses a significant risk to human well‐being. Currently, existing treatments for atherosclerosis lack sufficient efficiency, while the utilization of surface‐modified nanoparticles holds the potential to deliver highly effective therapeutic outcomes. These nanoparticles can target and bind to specific receptors that are abnormally over‐expressed in atherosclerotic conditions. This paper reviews recent research (2018–present) advances in various ligand‐modified nanoparticle systems targeting atherosclerosis by specifically targeting signature molecules in the hope of precise treatment at the molecular level and concludes with a discussion of the challenges and prospects in this field. The intention of this review is to inspire novel concepts for the design and advancement of targeted nanomedicines tailored specifically for the treatment of atherosclerosis.

Abstract Although immunotherapy has revolutionized cancer therapy by providing efficient tumor growth suppression, long‐term protection from recurrence as well as minimized side effects, the low response rate significantly limits the clinical application of immunotherapy in board types of solid tumors. In order to improve the therapeutic efficacy, conventional therapies including radiotherapy, chemotherapy, phototherapy and chemodynamic therapy are employed to combine with immunotherapy to elicit stronger antitumor immune responses. Polymer nanomedicines are frequently utilized in synergistic immunotherapy and other therapies owing to their tunable physiochemical properties, high drug loading capacity, ease of modification and low toxicity. With elaborate design and tailored properties, polymer nanomedicines can significantly enhance antitumor efficacy by enhancing tumor specificity, priming immune cells and amplifying immune responses in tumors. However, until now, there is no review solely dedicated to the comprehensive development of polymer‐based platforms for combinational immunotherapy of cancers. Herein, this paper summarizes latest advances in the design, fabrication and application of polymer nanomedicines in combinational immunotherapy and traditional antitumor strategies including radiotherapy, chemotherapy, photothermal therapy, photodynamic therapy and other therapies. An outlook on the trajectory and potential challenges of polymer nanomedicines in bridging the gap between immunotherapy and conventional therapies is also discussed.

Abstract Hexagonal boron nitride (h‐BN) nanomaterials are a rising star in the field of biomedicine. This review presents an overview of the progress in h‐BN nanomaterials for biological applications. It begins with a general introduction of the structural characteristics of h‐BN, followed by the brief introduction of its physical and chemical properties, including thermal, band and mechanical properties, chemical reactivity, biodegradability and biocompatibility, then emphasizes on the recent progress in the biomedical applications including drug delivery, boron neutron capture therapy (BNCT), bioimaging and nanozyme, and ends with the challenges and perspectives related to the biomedical applications. The advantages of BN nanomaterials used for biomedical applications were analyzed, and their problems were also discussed, inspiring the future rational designs of the BN nanomedicines.

Abstract Pelvic organ prolapse (POP) is one of the most common pelvic floor dysfunction disorders worldwide. The weakening of pelvic connective tissues initiated by excessive collagen degradation is a leading cause of POP. However, the patches currently used in the clinic trigger an unfavorable inflammatory response, which often leads to implantation failure and the inability to simultaneously reverse progressive collagen degradation. Therefore, to overcome the present challenges, a new strategy is applied by introducing puerarin (Pue) into poly(l‐lactic acid) (PLLA) using electrospinning technology. PLLA improves the mechanical properties of the patch, while Pue offers intrinsic anti‐inflammatory and pro‐collagen synthesis effects. The results show that Pue is released from PLLA@Pue in a sustained manner for more than 20 days, with a total release rate exceeding 80%. The PLLA@Pue electrospun patches also show good biocompatibility and low cytotoxicity. The excellent anti‐inflammatory and pro‐collagen synthesis properties of the PLLA@Pue patch are demonstrated both in vitro in H2O2‐stimulated mouse fibroblasts and in vivo in rat abdominal wall muscle defects. Therefore, it is believed that this multifunctional electrospun patch integrating anti‐inflammatory and pro‐collagen synthesis properties can overcome the limitations of traditional patches and has great prospects for efficient pelvic floor reconstruction.

Abstract Developing time‐sustained drug delivery systems is a main goal in innovative medicines. Inspired by the architecture of secretory granules from the mammalian endocrine system it has generated non‐toxic microscale amyloid materials through the coordination between divalent metals and poly‐histidine stretches. Like their natural counterparts that keep the functionalities of the assembled protein, those synthetic structures release biologically active proteins during a slow self‐disintegration process occurring in vitro and upon in vivo administration. Being these granules formed by a single pure protein species and therefore, chemically homogenous, they act as highly promising time‐sustained drug delivery systems. Despite their enormous clinical potential, the nature of the clustering process and the quality of the released protein have been so far neglected issues. By using diverse polypeptide species and their protein‐only oligomeric nanoscale versions as convenient models, a conformational rearrangement and a stabilization of the building blocks during their transit through the secretory granules, being the released material structurally distinguishable from the original source is proved here. This fact indicates a dynamic nature of secretory amyloids that act as conformational arrangers rather than as plain, inert protein‐recruiting/protein‐releasing granular depots.

Abstract Targeted delivery of anti‐tumor drugs and overcoming drug resistance in malignant tumor cells remain significant clinical challenges. However, there are only few effective methods to address these issues. Extracellular vesicles (EVs), actively secreted by cells, play a crucial role in intercellular information transmission and cargo transportation. Recent studies have demonstrated that engineered EVs can serve as drug delivery carriers and showed promising application prospects. Nevertheless, there is an urgent need for further improvements in the isolation and purification of EVs, surface modification techniques, drug assembly processes, and precise recognition of tumor cells for targeted drug delivery purposes. In this review, we summarize the applications of engineered EVs in cancer treatment and overcoming drug resistance, and current challenges associated with engineered EVs are also discussed. This review aims to provide new insights and potential directions for utilizing engineered EVs as targeted delivery systems for anti‐tumor drugs and overcoming drug resistance in the near future.

Abstract Layered double hydroxides (LDHs) have been widely studied for biomedical applications due to their excellent properties, such as good biocompatibility, degradability, interlayer ion exchangeability, high loading capacity, pH‐responsive release, and large specific surface area. Furthermore, the flexibility in the structural composition and ease of surface modification of LDHs makes it possible to develop specifically functionalized LDHs to meet the needs of different applications. In this review, the recent advances of LDHs for biomedical applications, which include LDH‐based drug delivery systems, LDHs for cancer diagnosis and therapy, tissue engineering, coatings, functional membranes, and biosensors, are comprehensively discussed. From these various biomedical research fields, it can be seen that there is great potential and possibility for the use of LDHs in biomedical applications. However, at the same time, it must be recognized that the actual clinical translation of LDHs is still very limited. Therefore, the current limitations of related research on LDHs are discussed by combining limited examples of actual clinical translation with requirements for clinical translation of biomaterials. Finally, an outlook on future research related to LDHs is provided.

Abstract The targeted drug delivery field is rapidly advancing, focusing on developing biocompatible nanoparticles that meet rigorous criteria of non‐toxicity, biocompatibility, and efficient release of encapsulated molecules. Conventional synthetic nanoparticles (SNPs) face complications such as elevated immune responses, complex synthesis methods, and toxicity, which restrict their utility in therapeutics and drug delivery. Extracellular vesicles (EVs) have emerged as promising substitutes for SNPs, leveraging their ability to cross biological barriers, biocompatibility, reduced toxicity, and natural origin. Notably, mesenchymal stem cell‐derived EVs (MSC‐EVs) have garnered much curiosity due to their potential in therapeutics and drug delivery. Studies suggest that MSC‐EVs, the central paracrine contributors of MSCs, replicate the therapeutic effects of MSCs. This review explores the characteristics of MSC‐EVs, emphasizing their potential in therapeutics and drug delivery for various diseases, including CRISPR/Cas9 delivery for gene editing. It also delves into the obstacles and challenges of MSC‐EVs in clinical applications and provides insights into strategies to overcome the limitations of biodistribution and target delivery.

Abstract Extracellular vesicles (EVs) are emerging as a promising drug delivery vehicle as they are biocompatible and capable of targeted delivery. However, clinical translation of EVs remains challenging due to the lack of standardized and scalable manufacturing protocols to consistently isolate small EVs (sEVs) with both high yield and high purity. The heterogenous nature of sEVs leading to unknown composition of biocargos causes further pushback due to safety concerns. In order to address these issues, we developed a robust quality‐controlled multi‐stage process to produce and isolate sEVs from human embryonic kidney HEK293F cells. We then compared different 2‐step and 3‐step workflows for eliminating protein impurities and cell‐free nucleic acids to meet acceptable limits of regulatory authorities. Our results showed that sEV production was maximized when HEK293F cells were grown at high‐density stationary phase in semi‐continuous culture. The novel 3‐step workflow combining tangential flow filtration, sucrose‐cushion ultracentrifugation and bind‐elute size‐exclusion chromatography outperformed other methods in sEV purity while still preserved high yield and particle integrity. The purified HEK293F‐derived sEVs were thoroughly characterized for identity including sub‐population analysis, content profiling including proteomics and miRNA sequencing, and demonstrated excellent preclinical safety profile in both in‐vitro and in‐vivo testing. Our rigorous enrichment workflow and comprehensive characterization will help advance the development of EVs, particularly HEK293F‐derived sEVs, to be safe and reliable drug carriers for therapeutic applications.

Abstract Background Honey exhibits a broad spectrum of antibacterial activity against Gram‐positive and Gram‐negative bacteria, including methicillin‐resistant Staphylococcus aureus (MRSA) ones. Chitosan (Cs) is a mucoadhesive polymer that also has antibacterial properties. Special attention has been paid to the design of polymeric nanoparticles (NPs) as new nano drug delivery systems to overcome bacterial resistance and its problems. Objectives The aim of the present study is to synthesize Cs‐meropenem NPs with/without honey as an antibiofilm and antibacterial agent to inhibit Staphylococcus aureus. Methods This study synthesized meropenem and honey‐loaded Cs nanogels and subsequently characterized them by Field Emission Scanning Electron Microscopy (FESEM), Fourier Transform Infrared Spectroscopy (FTIR), and DLS‐zeta potential. Using the broth microdilution and crystal violet assays, the antibacterial and antibiofilm activity of meropenem and honey‐loaded Cs nanogel, free meropenem, free honey, and free Cs NPs were investigated in vitro against MRSA strains. 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl‐2H‐tetrazolium bromide (MTT) was also used to test the cytotoxicity of several Cs‐NPs compound against the HEK‐293 regular cell line. Results The average size of meropenem and honey‐Cs‐NPs was reported to be 119.885 nm, and encapsulation efficiency was 88.33 ± 0.97 with stability up to 60 days at 4°C. The NPs showed enhanced antibiofilm efficacy against S. aureus at sub‐minimum inhibitory concentrations. Additionally, the cytotoxicity of meropenem and honey‐encapsulated Cs against the HEK‐293 normal cell line was insignificant. Conclusions Our findings suggested that meropenem and honey‐Cs‐NPs might be potential antibacterial and antibiofilm materials.

Abstract Precise and efficient regulation of microglia is vital for ischemic stroke therapy and prognosis. The infiltration of neutrophils into the brain provides opportunities for regulatory drugs across the blood–brain barrier, while hindered by neutrophil extracellular traps (NETs) and targeted delivery of intracerebral drugs to microglia. This study reports an efficient neutrophil hijacking nanoplatform (referred to as APTS) for targeted A151 (a telomerase repeat sequence) delivery to microglia without the generation of NETs. In the middle cerebral artery occlusion (MCAO) mouse model, the delivery efficiency to ischemic stroke tissues increases by fourfold. APTS dramatically reduces the formation of NETs by 2.2‐fold via reprogramming NETosis to apoptosis in neutrophils via a reactive oxygen species scavenging‐mediated citrullinated histone 3 inhibition pathway. Noteworthy, A151 within neutrophils is repackaged into apoptotic bodies following the death pattern reprogramming, which, when engulfed by microglia, polarizes microglia to an anti‐inflammatory M2 phenotype. After four times treatment, the cerebral infarction area in the APTS group decreases by 5.1‐fold. Thus, APTS provides a feasible, efficient, and practical drug delivery approach for reshaping the immune microenvironment and treating brain disorders in the central nervous system.

Abstract Sepsis poses a significant challenge in clinical management. Effective strategies targeting iron restriction, toxin neutralization, and inflammation regulation are crucial in combating sepsis. However, a comprehensive approach simultaneously targeting these multiple processes has not been established. Here, an engineered apoptotic extracellular vesicles (apoEVs) derived from macrophages is developed and their potential as multifunctional agents for sepsis treatment is investigated. The extensive macrophage apoptosis in a Staphylococcus aureus‐induced sepsis model is discovered, unexpectedly revealing a protective role for the host. Mechanistically, the protective effects are mediated by apoptotic macrophage‐released apoEVs, which bound iron‐containing proteins and neutralized α‐toxin through interaction with membrane receptors (transferrin receptor and A disintegrin and metalloprotease 10). To further enhance therapeutic efficiency, apoEVs are engineered by incorporating mesoporous silica nanoparticles preloaded with anti‐inflammatory agents (microRNA‐146a). These engineered apoEVs can capture iron and neutralize α‐toxin with their natural membrane while also regulating inflammation by releasing microRNA‐146a in phagocytes. Moreover, to exploit the microcosmic movement and rotation capabilities, erythrocytes are utilized to drive the engineered apoEVs. The erythrocytes‐driven engineered apoEVs demonstrate a high capacity for toxin and iron capture, ultimately providing protection against sepsis associated with high iron‐loaded conditions. The findings establish a multifunctional agent that combines natural and engineered antibacterial strategies.

Abstract Stimuli‐responsive DNA‐based logic gates have emerged as a promising field at the intersection of synthetic biology and nanotechnology. These gates exploit the unique properties of DNA molecules to perform programmable computational operations in response to specific stimuli. This review provides a comprehensive overview of recent advancements in the design, working principles, and applications of stimuli‐responsive DNA‐based logic gates. The progress made in developing various types of logic gates triggered by metal ions, pH, oligonucleotides, small molecules, proteins, and light is highlighted. The applications of these logic gates in imaging and biosensing, drug delivery, synthetic biology and molecular computing are discussed. This review underscores the significant contributions and future prospects of stimuli‐responsive DNA‐based logic gates in advancing the field of nanotechnology.

Abstract Rapid growth in nanoparticles (NPs) as delivery systems holds vast promise to promote therapeutic approaches for cancer treatment. Presently, a diverse array of NPs with unique properties have been developed to overcome different challenges and to achieve sophisticated delivery routes for enhancement of a series of therapies. Inspiring advances have been achieved in the field of cancer therapy using NPs. In this review, we aim to summarize the up‐to‐date progression of NPs for addressing various challenges, and expect to elicit novel and potential opportunities alternatively. We first introduce different sorts of NP technologies, illustrate their mechanisms, and present their applications. Then, the achievements made by NPs to break obstacles in delivering cargoes to specific sites through particular routes are highlighted, including long‐circulation, tumor targeting, responsive release, and subcellular localization. We subsequently retrospect recent research of NPs in different cancer treatments from single therapy, like chemotherapy, to combination therapy, like chemoradiotherapy, and to integrative therapy. Finally, the challenges and perspectives of NPs in cancer therapy, and their potential impact on the field of oncology are discussed. We believe this review can offer a deeper understanding of the challenges and opportunities of NPs for cancer therapy.

Abstract Cancer remains a leading cause of death worldwide, necessitating the development of innovative and more effective treatment strategies. Conventional cancer treatments often suffer from limitations such as systemic toxicity, poor pharmacokinetics, and drug resistance. Recently, there has been growing attention to utilizing natural compounds derived from various sources as possible cancer therapeutics. Natural compounds have demonstrated diverse bioactive properties, including antioxidant, anti‐inflammatory, and antitumor effects, making them attractive candidates for cancer treatment. However, their limited solubility and bioavailability present challenges for effective delivery to cancer cells. To overcome these limitations, researchers have turned to nanotechnology‐based drug delivery systems. Nanoparticles, with their small size and unique properties, can encapsulate therapeutic agents and offer benefits such as improved solubility, prolonged drug release, enhanced cellular uptake, and targeted delivery. Functionalizing nanoparticles with specific ligands further enhances their precision in recognizing and binding to cancer cells. Combining natural compounds with nanotechnology holds great promise in achieving efficient and safe cancer treatments by enhancing bioavailability, pharmacokinetics, and selectivity toward cancer cells. This review article provides an overview of the advancements in utilizing natural substances and nanotechnology‐based drug delivery systems for cancer treatment. It discusses the benefits and drawbacks of various types of nanoparticles, as well as the characteristics of natural compounds that make them appealing for cancer therapy. Additionally, current research on natural substances and nanoparticles in preclinical and clinical settings is highlighted. Finally, the challenges and future perspectives in developing natural compound‐nanoparticle‐based cancer therapies are discussed.

Abstract Background Elevated tumor tissue interstitial fluid pressure (IFP) is an adverse biomechanical biomarker that predicts poor therapy response and an aggressive phenotype. Advances in functional imaging have opened the prospect of measuring IFP non‐invasively. Image‐based estimation of the IFP requires knowledge of the tissue hydraulic conductivity (K), a measure for the ease of bulk flow through the interstitium. However, data on the magnitude of K in human cancer tissue are not available. Methods We measured the hydraulic conductivity of tumor tissue using modified Ussing chambers in surgical resection specimens. The effect of the tumor microenvironment (TME) on K was investigated by quantifying the collagen content, cell density, and fibroblast density of the tested samples using quantitative immune histochemistry. Also, we developed a computational fluid dynamics (CFD) model to evaluate the role of K on interstitial fluid flow and drug transport in solid tumors. Results The results show that the hydraulic conductivity of human tumor tissues is very limited, ranging from approximately 10−15 to 10−14 m2/Pa∙s. Moreover, K values varied significantly between tumor types and between different samples from the same tumor. A significant inverse correlation was found between collagen fiber density and hydraulic conductivity values. However, no correlation was detected between K and cancer cell or fibroblast densities. The computational model demonstrated the impact of K on the interstitial fluid flow and the drug concentration profile: higher K values led to a lower IFP and deeper drug penetration. Conclusions Human tumor tissue is characterized by a very limited hydraulic conductivity, representing a barrier to effective drug transport. The results of this study can inform the development of realistic computational models, facilitate non‐invasive IFP estimation, and contribute to stromal targeting anticancer therapies.

Abstract The biological barriers of the body, such as the blood–brain, placental, intestinal, skin, and air‐blood, protect against invading viruses and bacteria while providing necessary physical support. However, these barriers also hinder the delivery of drugs to target tissues, reducing their therapeutic efficacy. Extracellular vesicles (EVs), nanostructures with a diameter ranging from 30 nm to 10 μm secreted by cells, offer a potential solution to this challenge. These natural vesicles can effectively pass through various biological barriers, facilitating intercellular communication. As a result, artificially engineered EVs that mimic or are superior to the natural ones have emerged as a promising drug delivery vehicle, capable of delivering drugs to almost any body part to treat various diseases. This review first provides an overview of the formation and cross‐species uptake of natural EVs from different organisms, including animals, plants, and bacteria. Later, it explores the current clinical applications, perspectives, and challenges associated with using engineered EVs as a drug delivery platform. Finally, it aims to inspire further research to help bioengineered EVs effectively cross biological barriers to treat diseases.

Abstract Currently, there are no ex vivo systems that can model the motion of peripheral arteries and allow for the evaluation of pharmacokinetics (PK) of endovascular devices. The objective of this study was to develop a novel peripheral simulating bioreactor system to evaluate drug pharmacokinetics of stents. We utilized 3D‐printed and off‐the‐shelf components to construct a peripheral‐simulating bioreactor system capable of mimicking the motion of peripheral arteries. Servo motors were primarily used to shorten/elongate, twist, and bend explanted porcine carotid arteries. To evaluate the pharmacokinetics in the bioreactor, drug‐eluting stents were deployed within explanted arteries and subjected to vascular motion along with pulsatile flow conditions. Following 30 min and 24 h, the arteries were removed, and paclitaxel levels were measured. Scanning electron microscopy was also performed to evaluate the stent surface. Arterial paclitaxel levels of the stent‐treated arteries were found to be higher at 30 min than at 24 h following pulsatile and no vascular motion and even higher at 24 h following pulsatile flow and vascular motion. The residual drug on the stent significantly decreased from 30 min to 24 h. Scanning electron microscopy confirmed the loss of paclitaxel coating at 24 h and greater disturbance in stents under peripheral motion versus pulsatile only. This system represents the first ex vivo system to determine the PK of drug‐eluting stents under physiological flow and vascular motion conditions. This work provides a novel system for a quick and inexpensive preclinical tool to study acute drug tissue concentration kinetics of drug‐releasing interventional vascular devices designed for peripheral applications.