Purpose:Programmed Cell Death Protein 1 (PD-1) and Programmed Cell Death Ligand 1 (PD-L1) checkpoint blockade has led to improvements in clinical outcomes for various advanced cancers. However, response rates remain low, and most patients present with intrinsic resistance to PD-1/PD-L1 inhibitors. Circulating soluble PD-L1 (sPD-L1) has emerged as a driver of resistance to PD-1/PD-L1 inhibitors. Elevated levels of sPD-L1 can be detected in peripheral blood in patients with cancer and are associated with poor prognosis and resistance to PD-1/PD-L1 therapy, highlighting the need to find strategies to remove sPD-L1 from circulation. Here, we evaluated the efficacy and immunological responses of using NaNots®A, a type of engineered nanoparticle that has been designed to capture sPD-L1, as a therapeutic agent to treat cancer. Methods:Different biological samples containing sPD-L1 were tested pre- and post-treatment to determine the capturing efficiency of NaNots. To evaluate the therapeutic potential of NaNots in vivo, a humanized PD-L1 mouse model was used with an sPD-L1 secreting tumor model to assess tumor growth and to immunophenotype antitumor responses. Results:NaNot treatment successfully depleted sPD-L1 from multiple sources, including patient and mouse plasma. NaNot treatment resulted in substantial tumor growth delay and increased proportions of effector CD8 T cells, concurrent with decreased immunosuppressive regulatory T cells, in tumor and spleen tissues. Conclusion:Overall, this preclinical work demonstrates that selective capture of sPD-L1 in vivo with a novel nanotherapeutic platform can reduce immune suppression concurrent with greater immune activation, thereby enabling tumor growth control.
Periodontitis is a chronic inflammatory disease associated with obesity, type 2 diabetes, and cardiovascular disease, and has become a serious public health issue. Antibacterial treatment and mechanical debridement are the main treatment strategies for periodontitis. However, side effects and bacterial resistance might lead to treatment failure. Nanotechnology systems have new opportunities for the management of periodontitis. With benefits including superior targeting and fewer side effects, drug delivery systems constructed with nanoparticles (NPs) may provide local, delayed, and regulated drug release. When combined with immunomodulatory therapy, tissue regeneration, and antibacterial therapy, a high drug loading capacity of individual medications or therapeutic combinations is made possible by the large surface area to volume ratio of nanoparticles, providing synergistic beneficial effects. This paper reviews the progress in the research and application of nanoparticle-based drug delivery systems in the treatment of periodontitis. We focused on the pathophysiology of periodontitis, introduced the rational design of nano-drug delivery systems, and concentrated on the local approaches to treatment for periodontitis. Furthermore, the future challenges and research prospects for nanoparticle-based drug delivery systems in the treatment of periodontitis are also covered in this paper.
Gene silencing by RNA interference (RNAi) has emerged as a promising strategy for cancer therapy. Small interfering RNA (siRNA), a class of small regulatory RNAs that recognize and degrade complementary target messenger RNAs (mRNAs) in a sequence-specific manner at the post-transcriptional level, plays a critical role in regulating gene expression. However, the in vivo delivery of siRNA remains a formidable challenge due to its poor physiological stability, susceptibility to enzymatic degradation, inability to efficiently cross cellular membranes, non-specific off-target effects, and immunostimulation. Overcoming these barriers and enhancing the gene silencing efficiency of siRNA in target cells is essential for the clinical translation of RNAi technology. In recent years, tumor microenvironment (TME)-responsive nanocarriers have attracted considerable attention as a strategy to improve siRNA stability, enhance its enrichment and penetration at tumor sites, facilitate cellular uptake, and promote efficient gene silencing. This review comprehensively summarized the design principles and functional characteristics of TME-responsive siRNA delivery nanocarriers, with a focus on five major stimuli: pH, hypoxia, enzymes, glutathione (GSH), and reactive oxygen species (ROS). We critically analyze the advantages and limitations of existing nanocarrier systems, provide comparative insights through summary tables, and discuss future directions including multi-stimuli-responsive systems, combination therapies, and clinical translation challenges. This review aims to provide a systematic framework for understanding and advancing TME-responsive siRNA nanocarriers for tumor therapy.
Despite maximal safe resection and chemoradiotherapy, glioblastoma almost invariably recurs near the resection margin. Incomplete tumor removal is only one contributor; infiltrative residual cells, resistant stem-like states, wound-healing responses, local immunosuppression, and limited drug access also promote regrowth. This review examines stand-alone nanocarriers and nano-enabled composites in which nanoscale components are incorporated into hydrogels, scaffolds, or implants at the postoperative cavity-margin interface. Biomaterials lacking a functional nanoscale component are included only as design or procedural comparators. Postoperative resection models are distinguished from intratumoral, unresected orthotopic, ex vivo, and in vitro studies, which provide indirect support. Most evidence of efficacy remains preclinical, whereas human studies mainly address feasibility, safety, pharmacodynamic activity, or workflow precedent. Translation depends on reproducible retention, margin coverage, biologically matched release, brain safety, scalable manufacturing, and neurosurgical compatibility. Local nanomedicine thus remains a conditional postoperative strategy whose clinical value has yet to be established.
Glycyrrhizic acid (GL) and glycyrrhetinic acid (GA) exhibit antitumor activity, favorable biocompatibility, receptor-targeting capabilities, and amphiphilicity. These properties make them promising multifunctional components for developing antitumor drug delivery systems. Unlike previous reviews that focus on individual applications, this review systematically categorizes GL/GA according to their three functional roles. First, as therapeutic agents, GL/GA can be incorporated into passively targeted, actively targeted, and stimuli-responsive nanocarriers. They can be combined with chemotherapeutic drugs, such as cisplatin and paclitaxel, to enhance therapeutic efficacy and reduce systemic toxicity. Second, as targeting ligands, GL/GA can be conjugated to the surfaces of nanocarriers to enable receptor-mediated tumor delivery. Finally, as self-assembling materials, GL/GA can co-assemble with other drugs to form carrier-free nanostructures. Alternatively, they can serve as building blocks for polymeric carriers. These strategies enable drug-carrier integration, simplify formulation processes, and enhance synergistic antitumor effects. Furthermore, this review analyzes the key challenges in the clinical translation of these formulations. These challenges include the complexity of large-scale production, insufficient in vivo stability, a lack of long-term safety data, and inconsistencies in quality evaluation systems. Future translational prospects are also outlined to guide the rational design and clinical development of natural product-based nanomedicines.
Cancer poses an escalating threat to global public health, characterized by continuous rises in both incidence and mortality. While conventional tumor interventions including surgery, chemotherapy and radiotherapy have made considerable progress, their clinical efficacy is severely constrained by systemic toxic side effects, inadequate targeting precision and frequent severe postoperative and treatment-related sequelae. Nanodrug delivery systems have evolved as a viable therapeutic alternative to optimize tumor targeting and minimize systemic toxicity. However, conventional nanocarriers suffer from rapid clearance by the mononuclear phagocyte system, and the intricate, heterogeneous tumor microenvironment (TME) further impairs effective intratumoral drug penetration and uniform distribution. As an emerging class of living delivery vectors, probiotics have recently gained extensive research attention by virtue of their intrinsic tumor tropism, unique capacity to adapt to and remodel the TME, and excellent synergistic compatibility with multiple therapeutic regimens. This review systematically elaborates the biological mechanisms governing the tumor-targeted accumulation and TME-responsive properties of probiotics, summarizes core strategies for probiotic genetic modification and hybrid system construction, and compares the strengths and applicable scenarios of diverse probiotic chassis strains. We further discuss the synergistic potential of probiotic-based platforms combined with immunotherapy, chemotherapy, radiotherapy and physical therapy. Finally, this article underscores the key bottlenecks and future research directions for the clinical translation of probiotic-based antitumor therapeutics, aiming to provide rigorous theoretical support for their broader clinical application in cancer treatment.
Diabetic chronic wounds (DCWs) are difficult to heal due to the synergistic effects of bacterial infection, immune dysregulation, persistent oxidative stress, and microcirculatory impairment, posing a major challenge in tissue regeneration. Self-assembled hydrogels (SAHs), owing to their molecular programmability, tunable network architectures, and ability to respond to the pathological wound microenvironment, have demonstrated unique advantages in the repair of complex chronic wounds. This review summarizes the roles of various interactions, including hydrogen bonding, π-π stacking, metal coordination, hydrophobic interactions, electrostatic interactions, and dynamic covalent bonds, in constructing three-dimensional hydrogel networks. It further discusses the main design strategies and biological functionalities of SAHs, encompassing short peptides, polysaccharides, metal ions, nucleic acids, cyclodextrins (CDs), and dynamic covalent crosslinking materials. This review focuses on the pathological characteristics of DCWs and highlights recent research progress on SAHs in antibacterial, anti-inflammatory, antioxidative, immunomodulatory, pro-angiogenic, and tissue regeneration applications. Although various SAHs have demonstrated promising therapeutic efficacy in preclinical animal models, clinical practice still largely relies on conventional hydrogel formulations. Future efforts should focus on strengthening the integration between material design and pathological mechanisms, as well as establishing standardized evaluation frameworks, to facilitate the clinical translation of SAHs for the treatment of DCWs.
The mismatch between the low oral bioavailability of many phytochemicals and their broad systemic efficacy remains a central challenge for natural-product pharmacology and nanomedicine. Rather than relying solely on direct drug-target interactions at distant tissues, accumulating evidence suggests that phytochemicals can act at primary interfaces such as the intestinal epithelium, liver, tumor stroma, and immune microenvironment to alter EV biogenesis or cargo in selected models, while effects on tissue homing remain largely proposed. In this review, we discuss these findings from a vesicle-enabled nanomedicine perspective, highlighting how phytochemical-primed host EVs and plant-derived exosome-like nanoparticles (PELNs) may function as biogenic signal carriers that translate local chemical exposure into systemic therapeutic regulation. We summarize reported links between bioactive compounds and EV release, cargo loading, and membrane remodeling, while distinguishing directly demonstrated mechanisms from proposed ones. We further discuss how surface molecules including integrins and tetraspanins shape organotropism, blood-brain barrier transport, tumor pre-metastatic niche formation, and gut-liver or neuro-vascular communication. Special attention is given to the translational value of EVs and PELNs as natural nanocarriers for poorly soluble phytochemicals, as liquid-biopsy biomarkers of treatment response, and as quality-controllable platforms for traditional Chinese medicine (TCM)-derived interventions. Here, "vesicular information" refers to the measurable molecular cargo and surface features of a vesicle preparation. This emerging model does not yet establish that phytochemical-modified EVs explain the bioavailability paradox in all settings.
Skin diseases are characterized by complex pathophysiology and substantial clinical heterogeneity. Their onset and progression involve multiple interconnected processes, including oxidative stress, chronic inflammation, disruption of the skin barrier, microbial dysbiosis, and impaired tissue repair, which often limit the ability of conventional therapies to achieve sustained disease control. Selenium nanoparticles (SeNPs) offer distinct advantages in dermatological treatment by combining the intrinsic biological activities of selenium, such as redox regulation and immunomodulation, with the engineering versatility of nanomaterials. However, therapeutic approaches that rely solely on the inherent bioactivity of SeNPs are increasingly insufficient to address the complexity of disease-associated microenvironments. Accordingly, the development of SeNPs into intelligent, multifunctional therapeutic platforms has emerged as an important direction in this field. Existing reviews have largely focused on the biological functions, preparation methods, or broad biomedical applications of SeNPs, whereas the engineering principles underlying their transition from intrinsically active nanomaterials to intelligent dermatological therapeutic platforms have not been systematically examined. This review therefore focuses on how the intrinsic functions of selenium can be translated, through materials and delivery engineering, into platform-level capabilities relevant to the treatment of skin diseases. By linking disease-specific pathological features and delivery barriers with corresponding design strategies, we propose a mechanism-guided framework for the rational development of SeNP-based dermatological nanomedicines.
Purpose:To develop a pH/ROS dual-responsive nanoplatform based on polyurethane (PU) and poly(L-lysine) (PLys) copolymers for targeted leonurine (Leo) delivery and to evaluate its anti-inflammatory and cartilage-protective effects in experimental rheumatoid arthritis (RA). Methods:PLys-modified PU polymers were grafted with 2,3-dimethylmaleic anhydride (DMMA) and incorporated with redox-cleavable thioether bonds to construct pH/ROS dual-responsive nanoparticles (PU-MA@Leo) through self-assembly. The physicochemical properties and stimulus-responsive behavior of the nanoparticles were evaluated under physiological and inflammatory conditions. Their anti-inflammatory and cartilage-protective effects were further assessed through in vitro and in vivo experiments, with a particular focus on macrophage-mediated inflammation, oxidative stress, inflammatory mediator production, and the JAK2/STAT3 signaling pathway. Results:PU-MA@Leo nanomicelles exhibited a leonurine drug-loading content of 21.17 ± 1.26% and an encapsulation efficiency of 63.85 ± 1.11%, compared with 17.60 ± 0.53% and 53.87 ± 0.96%, respectively, for PU@Leo. The formulations showed hemolysis rates below 1% and remained stable under physiological conditions. Acidic conditions induced DMMA cleavage and surface-charge conversion, whereas ROS exposure promoted thioether oxidation, micellar destabilization, and accelerated leonurine release. PU-MA showed enhanced uptake by activated macrophages. PU-MA@Leo reduced the expression of inflammatory mediators and was accompanied by decreased phosphorylation of JAK2 and STAT3. In the murine CIA model, rhodamine-labelled PU-MA micelles exhibited enhanced accumulation and fluorescence retention at arthritic joints. During the 27-day experimental period, PU-MA@Leo reduced arthritis severity and paw swelling and attenuated bone erosion, synovial inflammation, and cartilage damage compared with free leonurine and blank micelles. Conclusion:The pH/ROS-responsive PU-MA@Leo nanoplatform improved leonurine delivery to inflamed joints and demonstrated promising short-term anti-inflammatory and chondroprotective efficacy in murine experimental RA. These findings support further preclinical evaluation of this platform in human-relevant models, together with pharmacokinetic, biodistribution, long-term safety, immunogenicity, and post-treatment durability studies.
Background:Cationic highly branched poly(β-amino ester)s (HPAEs) represent a promising class of nonviral gene-delivery polymers; however, their in vivo distribution and biological fate remain challenging to monitor. Here, we explored covalent conjugation of indocyanine green (ICG) as a strategy to impart near-infrared-I (NIR-I) fluorescence to HPAEs while maintaining their DNA complexation capacity and gene-delivery performance. Methods:HPAE was modified with increasing feed amounts of ICG-N-hydroxysuccinimide (ICG-NHS), generating a series of fluorescent polymers designated HPAE-0, HPAE-1, HPAE-3, HPAE-5, HPAE-7, and HPAE-9, where the numerical suffixes indicate ICG-NHS feed volumes rather than substitution ratios. The resulting conjugates and their DNA nanoparticles were characterized by spectroscopic and chromatographic analyses, DNA-binding assays, dynamic light scattering, zeta-potential measurements, transmission electron microscopy, and optical-stability evaluation. In vitro gene-delivery activity and cytocompatibility were assessed in multiple cell models, while systemic distribution, biocompatibility, and tissue responses were evaluated in healthy BALB/c mice following administration. Results:Increasing ICG-NHS feed resulted in tunable incorporation of fluorescent moieties into the HPAE backbone. Among the tested formulations, HPAE-3 exhibited an apparent amine substitution degree of 18.98% ± 0.54% and a fluorescence emission maximum at approximately 834 nm. HPAE-3-based nanoparticles displayed favorable physicochemical properties, including hydrodynamic diameters of approximately 170-290 nm, low-to-moderate dispersity (PDI, 0.18-0.40), positive surface potentials (+23 to +40 mV), and efficient DNA condensation at polymer/DNA ratios ≥20:1. Importantly, ICG incorporation at this level preserved reporter-gene expression in HEK293T, RAW264.7, and MLE-12 cells while maintaining acceptable cytocompatibility. Following systemic administration in mice, HPAE-3 mediated luciferase reporter-gene expression predominantly in the liver, spleen, and lungs. HPAE-3-associated NIR-I fluorescence was most evident in the liver and lungs at 6 h, with a weaker signal in the spleen, and declined thereafter; by 72 h, residual ex vivo fluorescence was detected predominantly in the liver. No apparent acute tissue damage, significant alterations in serum biochemical parameters, or deviations in body-weight profiles were observed compared with control groups. Conclusion:HPAE-3 achieved a balanced integration of NIR-I fluorescence, DNA-delivery capability, nanoparticle stability, and preliminary in vivo tolerability. These results establish ICG-labeled HPAE as a potential platform for noninvasive visualization of polymer-mediated gene delivery and provide a foundation for further investigation of its biodistribution, intracellular fate, and therapeutic applications.
Hydrogels have found extensive applications in the medical field owing to their designability, biocompatibility, and self-supporting characteristics. Natural products, possessing multiple pharmacological activities and relatively low toxicity compared to chemical drugs, exhibit unique advantages in the field of hydrogel-related therapy. This review examines three major design strategies for natural product-based hydrogels from the perspective of how natural products interact with hydrogel networks: self-assembly of natural small molecules, physical encapsulation of natural products, and chemical conjugation of natural products to polymer matrices. These strategies determine the forms in which natural products are incorporated into hydrogels. Natural products may be encapsulated as bioactive components, participate in gelation behavior as matrices or crosslinking agents, or form nanoparticles embedded within the hydrogels. This review further analyzes the effects of these design strategies on hydrogel mechanical properties, retention of biological activity and drug-release behavior, and summarizes their application characteristics in biomedical fields. Finally, the advantages, limitations, and development prospects of the different design strategies are discussed. This review aims to provide guidance for the rational design, synthesis, and application of natural product hydrogels according to the properties of natural products and specific biomedical requirements.
Purpose:Efficient nanocarrier design for tumour targeting requires understanding drug binding, release, and membrane interactions. This study presents the first all-atom molecular dynamics simulations of curcumin-loaded cellulose nanofibers (CNFs) interacting with healthy and breast cancer cell membranes, supported by experimental evaluation. Methods:Simulations were performed on curcumin-loaded cylindrical and planar CNFs docked onto modelled healthy and breast cancer-mimicking lipid bilayers, followed by assessing binding energetics, structural stability, solvent exposure, and molecular mobility. Experimentally, free and curcumin-loaded CNFs were fabricated, characterized, and evaluated for encapsulation efficiency, in vitro release, and cytotoxicity. Results:Computational results showed that both arrangements interacted more favourably with cancer membranes than healthy models. In cylindrical systems, curcumin exhibited reduced mobility, increased localization, and partial penetration into cancer membranes, whereas planar systems favoured continued drug association with the nanocarrier and stronger membrane interaction. According to the experimental results, uniform CNFs achieved 82% encapsulation efficiency and showed biphasic release behaviour. Blank CNFs were biocompatible, while curcumin-loaded CNFs induced concentration- and time-dependent cytotoxicity in MCF-7 cells. Conclusion:Findings highlight the importance of membrane composition and nanofiber arrangement in regulating drug release and therapeutic performance, providing insights for rational nanocarrier design in cancer drug delivery.
Zeolitic imidazolate framework-8 (ZIF-8)-based biomaterials are increasingly investigated for bone repair because they combine cargo loading, environment-dependent degradation, surface engineering, and bioactive Zn2+ release. However, recent reviews already catalogue the multifunctional design and orthopedic applications of ZIF-8, while the directness of evidence supporting specific osteoimmunomodulatory claims remains less clear. This structured narrative review critically appraises preclinical ZIF-8 literature using a predefined evidence-classification framework that separates direct ZIF-8 evidence in bone-related models from indirect evidence derived from in vitro or non-bone studies, zinc biology, or other biomaterials, and from proposed mechanisms lacking direct validation. Macrophage-centered immunomodulation currently has the clearest direct support, including studies linking ZIF-8-containing systems to changes in inflammatory signaling and repair-associated macrophage phenotypes alongside bone regeneration. By contrast, direct evidence for local Th17/Treg regulation, neutrophil extracellular trap modulation, and broader immune-cell networks remains limited; these pathways should therefore be treated primarily as mechanistic hypotheses or future research directions. We also examine whether reported effects can be attributed to the ZIF-8 carrier itself, released Zn2+, loaded cargo, surface coatings, or composite matrices, and summarize study-level information on formulation, release conditions, dose, models, controls, immune endpoints, and regenerative outcomes. Particular attention is given to medium-dependent ZIF-8 stability, including phosphate and biological-fluid effects, dose-dependent cytotoxicity, the uncertain fate of Zn2+ and 2-methylimidazole, bone targeting versus local retention, and the scarcity of long-term pharmacokinetic, biodistribution, and large-animal data. Finally, we propose a translational-readiness framework spanning component attribution, standardized dose-release-toxicity testing, disease-specific validation, manufacturing reproducibility, sterilization, and regulatory planning. Most available evidence remains proof-of-concept and preclinical, indicating that mechanistic and safety validation should precede claims of clinical readiness.
Background:Cardiac sympathetic hyperactivation of the left stellate ganglion (LSG) critically promotes ventricular arrhythmias (VAs) following myocardial infarction (MI). Although neuromodulatory strategies targeting sympathetic activity have shown therapeutic potential, current strategies are limited by invasiveness, incomplete targeting and transient efficacy. Therefore, safe and precise approaches for modulating LSG activity are needed. This study aimed to investigate the enhanced neuromodulatory effects of phospholipid-coated carbon nanotubes (PC-CNTs) combined with near-infrared (NIR) photothermal therapy on the LSG for preventing post-MI VAs. Methods:PC-CNTs were synthesized and characterized, followed by evaluation of their photothermal properties and in vitro/in vivo biocompatibility. In a canine MI model induced by left anterior descending artery occlusion (n = 18), animals were randomly assigned to PBS, PC-CNTs and PC-CNTs + NIR groups. PBS or PC-CNTs (30 μg mL-1, 0.1 mL) were locally microinjected into the LSG, and animals in the PC-CNTs + NIR group subsequently received 808 nm NIR laser irradiation (1.0 W cm-2 for 5 min). LSG neural activity, heart rate variability (HRV), ventricular effective refractory period (ERP) and VA incidence were assessed. Transcriptomic profiling of LSG tissue and molecular analysis of peri-ganglionic adipose tissue were performed to evaluate therapeutic effects and potential mechanisms. Results:PC-CNTs exhibited excellent photothermal conversion efficiency and favorable biocompatibility. In vivo, PC-CNTs treatment suppressed MI-induced LSG hyperactivity, improved cardiac autonomic balance, enhanced ventricular electrophysiological stability and reduced VA susceptibility compared with the PBS group. The addition of NIR photothermal therapy further enhanced these protective effects, resulting in further suppression of sympathetic activation and reduction of post-MI arrhythmias. Molecular analyses suggested that combined PC-CNTs and NIR treatment modulated the LSG microenvironment, as evidenced by reduced expression of inflammation-related genes (CXCL14, CSF3, TIMP1 and CRLF1), indicating attenuation of neuroinflammatory signaling. Additionally, NIR-induced local hyperthermia was associated with thermogenic browning of peri-ganglionic white adipose tissue, characterized by increased expression of thermogenic markers and reduced adipocyte size. These changes may contribute to reduced sympathetic hyperactivity and decreased arrhythmia susceptibility. Conclusion:The combination of PC-CNTs and NIR photothermal therapy provides enhanced anti-arrhythmic effects associated with suppression of LSG hyperactivity and modulation of neuroinflammatory signaling and peri-ganglionic adipose browning, representing a promising preclinical strategy for preventing VAs.
The pathogenesis of osteoporosis is primarily associated with impaired communication between osteoblasts and osteoclasts, leading to disrupted bone homeostasis. Conventional biomaterials mainly rely on macroscopic structural support and are limited in their ability to precisely regulate the complex bone microenvironment and overcome biological barriers. As representative soft matter nanoplatforms, nanogels possess unique viscoelastic mechanical properties and adaptive biointerfacial properties, offering new opportunities to overcome physical barriers within bone tissues. Moving beyond previous studies that primarily focused on the passive structural support provided by macroscopic hydrogels, this review presents a micro-nano-bio interfacial perspective to systematically elucidate the roles of nanogels in precision therapy for bone disorders. Considering the spatial constraints of the lacunar-canalicular system (LCS), with canalicular diameters of approximately 100-300 nm, we highlight how the stress relaxation behavior and deformation modulus of nanogels jointly determine their migration and penetration efficiency within confined spaces. Furthermore, nanogels can function as dynamic biomimetic systems that sense alterations in the bone microenvironment and actively regulate immune and metabolic homeostasis within bone tissue. This review summarizes engineering strategies for nanogel development, including optimization of network architectures, hierarchical surface targeting, and multi-responsive drug release mechanisms. In addition, the effects of protein corona formation and biological barriers on the in vivo fate and therapeutic performance of nanogels are critically discussed. Finally, from a translational perspective, we evaluate the therapeutic potential and key challenges of nanogels in precision bone regeneration and propose design principles for next-generation bone-targeted nanomedicines based on mechanical adaptation, biointerface engineering, and intelligent responsiveness.
Breast cancer remains one of the leading causes of cancer-related mortality worldwide, with its marked molecular heterogeneity and therapeutic resistance continuing to limit long-term clinical success. Although advances in targeted therapies have improved patient outcomes, tumor recurrence, systemic toxicity, and drug resistance remain major clinical challenges. MicroRNAs (miRNAs) have emerged as promising therapeutic molecules because they regulate multiple oncogenic pathways involved in proliferation, apoptosis, epithelial-mesenchymal transition, metastasis, and therapy resistance. Preclinical studies have demonstrated that restoring tumor-suppressive miRNAs or inhibiting oncogenic miRNAs can suppress tumor growth, reduce metastatic potential, and enhance treatment sensitivity. However, their clinical application is hindered by poor stability, rapid enzymatic degradation, limited cellular uptake, and inefficient intracellular delivery. Recent advances in nanomedicine have enabled the development of multifunctional nanoparticle platforms that effectively address these limitations. Lipid nanoparticles, polymeric nanoparticles, dendrimers, and inorganic nanocarriers have demonstrated the ability to protect miRNAs from degradation, prolong systemic circulation, enhance tumor-specific accumulation, facilitate cellular uptake, and promote endosomal escape for efficient cytoplasmic release. Moreover, targeted and stimuli-responsive nanocarriers, as well as combination strategies integrating miRNAs with conventional therapeutics, have shown encouraging therapeutic efficacy in preclinical breast cancer models. This review summarizes recent advances in nanoparticle-mediated miRNA delivery systems for breast cancer, highlighting the biological roles of therapeutic miRNAs, the design and performance of current nanocarriers, and their translational potential. Current challenges and future perspectives for the clinical implementation of miRNA-based nanomedicine are also discussed. Overall, nanoparticle-enabled miRNA therapeutics represent a promising platform for advancing precision medicine and next-generation personalized treatment strategies for breast cancer.
Diabetic chronic wounds have emerged as a major global public health challenge due to a self-perpetuating vicious cycle driven by interconnected pathological factors. Conventional treatment strategies, such as surgical debridement and standard dressings, often fail to effectively penetrate the biofilm barrier or simultaneously modulate the complex wound microenvironment, resulting in limited therapeutic efficacy and an increased risk of drug resistance. The advent of nanotechnology offers a revolutionary tool to address this dilemma. Leveraging their unique size effects, facile functionalization, and stimuli-responsive properties, nanomaterials can be engineered into multifunctional platforms for the active modulation of the wound microenvironment. This review systematically summarizes three cutting-edge strategies for nano-based wound dressings in the management of diabetic wound infections, including nanozyme catalytic therapy, nano-microneedle synergistic delivery systems, and Janus-structured intelligent fluid management, aiming to elucidate the mechanisms of action, synergistic rationale, and clinical translational prospects of these strategies.
Colorectal cancer (CRC) remains difficult to treat because redox adaptation, metabolic plasticity, mucin-associated delivery barriers, immune exclusion, and microbiota-dependent signaling jointly limit conventional therapy. Engineered nanozymes provide a reaction-centered strategy for exploiting these CRC-specific vulnerabilities. This review critically compares metal, metal-oxide, carbon-based, porous-framework, and single-atom nanozymes with respect to catalytic mechanism, enzyme-mimicking activity, substrate dependence, controllability, biosafety, and translational suitability. We examine how acidity, hydrogen peroxide, hypoxia, glutathione enrichment, metabolic dysregulation, mucin barriers, and the gut microbiota influence catalytic performance. We further evaluate evidence for chemotherapy sensitization, chemodynamic, photothermal, photodynamic, sonodynamic, immunotherapeutic, and multimodal treatment, emphasizing both mechanistic synergy and limitations of the available preclinical models. Major translational barriers include non-standardized catalytic assays, heterogeneous intratumoral substrates, off-target reactive oxygen species toxicity, uncertain degradation and long-term fate, microbiome disruption, manufacturing reproducibility, and limited validation in orthotopic, immunocompetent, organoid, and patient-derived systems. We therefore position CRC nanozyme therapy as a disease-oriented catalytic medicine platform whose clinical value will depend on biomarker-guided selection, programmable activation, and degradable, locally controllable designs.
Purpose:Osteoporosis is characterized by an acidic and oxidative stress microenvironment driven by excessive osteoclast activity, which impairs osteogenesis and leads to dysregulated bone remodeling. This study aims to develop selenium-doped calcium hydroxide nanoparticles (SeCaNP) to simultaneously inhibit osteoclastogenesis and promote osteogenic differentiation, thereby providing a multi-targeted microenvironment-modulating strategy for osteoporosis therapy. Methods:SeCaNP was synthesized via a coprecipitation method and characterized using TEM, XRD, and acid-neutralization assays. In vitro, bone marrow-derived macrophages (BMMs) and bone marrow mesenchymal stem cells (BMSCs) were co-cultured with SeCaNP to assess osteoclast activity and osteogenic differentiation. In vivo, an ovariectomy (OVX)-induced osteoporosis mouse model was established and treated with local injections of SeCaNP. Therapeutic efficacy and biosafety were systematically evaluated. Results:SeCaNP significantly upregulated GPx1 expression, effectively scavenged reactive oxygen species (ROS), and neutralized the intracellular acidic microenvironment, thereby markedly inhibiting osteoclastogenesis. Concurrently, SeCaNP promoted BMSC cytoskeletal remodeling and significantly enhanced osteogenic differentiation and mineralization, upregulating key markers (RUNX2, ALP, OPN, OCN). RNA-seq analysis indicated that SeCaNP regulated osteogenesis-related membrane signaling platforms and extracellular matrix assembly. In vivo, SeCaNP treatment significantly ameliorated OVX-induced bone loss, notably improving bone mineral density (BMD) and trabecular microarchitecture parameters (BV/TV, Tb.N, Tb.Th). Furthermore, SeCaNP upregulated BMP-2 expression and serum BALP levels without inducing systemic toxicity. Conclusion:SeCaNP effectively overcomes the limitations of conventional osteoporosis therapies by integrating acid neutralization, antioxidant properties, and osteogenic support. Through a dual-regulatory mechanism that inhibits bone resorption and promotes bone formation, SeCaNP successfully reconstructs the pathological bone microenvironment and reverses bone loss, highlighting its significant potential as a microenvironment-modulating biomaterial for anti-osteoporotic therapy.
