Despite their potential, the adoption of nanotechnology in therapeutics remains limited, with only around eighty nanomedicines approved in the past 30 years. This disparity is partly due to the "one-size-fits-all" approach in medical design, which often overlooks patient-specific variables such as biological sex, genetic ancestry, disease state, environment, and age that influence nanoparticle behavior. Nanoparticles (NPs) must be transported through systemic, microenvironmental, and cellular barriers that vary across heterogeneous patient populations. Key patient-dependent properties impacting NP delivery include blood flow rates, body fat distribution, reproductive organ vascularization, hormone and protein levels, immune responses, and chromosomal differences. Understanding these variables is crucial for developing effective, patient-specific nanotechnologies. The formation of a protein corona around NPs upon exposure to biological fluids significantly alters NP properties, affecting biodistribution, pharmacokinetics, cytotoxicity, and organ targeting. The dynamics of the protein corona, such as time-dependent composition and formation of soft and hard coronas, depend on NP characteristics and patient-specific serum components. This review highlights the importance of understanding protein corona formation across different patient backgrounds and its implications for NP design, including sex, ancestry, age, environment, and disease state. By exploring these variables, we aim to advance the development of personalized nanomedicine, improving therapeutic efficacy and patient outcomes.

Owing to their unique physiochemical properties, low toxicity, antipathogenic effects and tunability, fluorescent carbon quantum dots (CQDs) represent a new generation of carbon-based nanomaterials. Despite the mounting research on the efficacy of CQDs against resilient plant pathogens, their potential ability to mitigate viral pathogens and the underlying molecular mechanism(s) remain understudied. In this study, we optimized the CQDs to maximize their antiviral effects against a highly pathogenic Begomovirus (cotton leaf curl Multan virus, CLCuMuV) and elucidated the mechanistic pathways associated with CQDs-mediated viral inhibition. To fine-tune the CQDs-induced antiviral effects against CLCuMuV and investigate the underlying molecular mechanisms,we used HR-TEM, XRD, FT-IR, XPS, and UV‒Vis spectrophotometry to characterize the CQDs. SPAD and FluorCam were used for physiological and photosynthetic performance analysis. Transcriptome, RT‒qPCR, integrated bioinformatics and molecular biology were employed to investigate gene expression, viral quantification and data validation.

Seed coating with fungicides is a common practice in controlling seed-borne diseases, but conventional methods often result in high toxicity to plants and soil. In this study, a nanoparticle formulation was successfully developed using the metal-organic framework UiO-66 as a carrier of the fungicide ipconazole (IPC), with a tannic acid (TA)-Zn coating serving as a protective layer. The IPC@UiO-66-TA-Zn nanoparticles provided a controlled release, triggered and regulated by environmental factors such as pH and temperature. This formulation efficiently controlled the proliferation of Fusarium fujikuroi spores, with high penetration into both rice roots and fungal mycelia. The product exhibited high antifungal activity, achieving control efficacy rates of 84.09% to 93.10%, low biotoxicity, and promoted rice growth. Compared to the IPC flowable suspension formula, IPC@UiO-66-TA-Zn improved the physicochemical properties and enzymatic activities in soil. Importantly, it showed potential for mitigating damage to beneficial soil bacteria. This study provides a promising approach for managing plant diseases using nanoscale fungicides in seed treatment.

Nanotechnology holds immense promise in revolutionising healthcare, offering unprecedented opportunities in diagnostics, drug delivery, cancer therapy, and combating infectious diseases. This review explores the multifaceted landscape of nanotechnology in healthcare while addressing the critical aspects of safety and environmental risks associated with its widespread application. Beginning with an introduction to the integration of nanotechnology in healthcare, we first delved into its categorisation and various materials employed, setting the stage for a comprehensive understanding of its potential. We then proceeded to elucidate the diverse healthcare applications of nanotechnology, spanning medical diagnostics, tissue engineering, targeted drug delivery, gene delivery, cancer therapy, and the development of antimicrobial agents. The discussion extended to the current situation surrounding the clinical translation and commercialisation of these cutting-edge technologies, focusing on the nanotechnology-based healthcare products that have been approved globally to date. We also discussed the safety considerations of nanomaterials, both in terms of human health and environmental impact. We presented the in vivo health risks associated with nanomaterial exposure, in relation with transport mechanisms, oxidative stress, and physical interactions. Moreover, we highlighted the environmental risks, acknowledging the potential implications on ecosystems and biodiversity. Lastly, we strived to offer insights into the current regulatory landscape governing nanotechnology in healthcare across different regions globally. By synthesising these diverse perspectives, we underscore the imperative of balancing innovation with safety and environmental stewardship, while charting a path forward for the responsible integration of nanotechnology in healthcare.

RNA therapeutics, such as mRNA, siRNA, and CRISPR-Cas9, present exciting avenues for treating diverse diseases. However, their potential is commonly hindered by vulnerability to degradation and poor cellular uptake, requiring effective delivery systems. Lipid nanoparticles (LNPs) have emerged as a leading choice for in vivo RNA delivery, offering protection against degradation, enhanced cellular uptake, and facilitation of endosomal escape. However, LNPs encounter numerous challenges for targeted RNA delivery in vivo, demanding advanced particle engineering, surface functionalization with targeting ligands, and a profound comprehension of the biological milieu in which they function. This review explores the structural and physicochemical characteristics of LNPs, in-vivo fate, and customization for RNA therapeutics. We highlight the quality-by-design (QbD) approach for targeted delivery beyond the liver, focusing on biodistribution, immunogenicity, and toxicity. In addition, we explored the current challenges and strategies associated with LNPs for in-vivo RNA delivery, such as ensuring repeated-dose efficacy, safety, and tissue-specific gene delivery. Furthermore, we provide insights into the current clinical applications in various classes of diseases and finally prospects of LNPs in RNA therapeutics.

Oxidative stress is a major pathological factor that impedes the diabetic wound healing process. Procyanidins (PC) form nanoparticle-vesicles (PPNs) through hydrogen bonding and exhibit good drug delivery capability; however, their application in diabetic wounds is unsatisfactory. To meet the antioxidant needs for treating, high-throughput screening in the natural product library (NPL) under in vitro oxidative stress conditions was conducted to enhance the antioxidant activity of PPNs. HUVECs treated with tert-Butyl Hydroperoxide (TBHP) were established as screening model in vitro. Baicalein (BAI) was identified from over 600  products in the library as the most effective one to combat oxidative stress. Further study showed that PC and BAI may react in equal proportions to synthesize new vesicles, named BAI-PC Polyphenolic nanovesicles (BPPNs), which possess reactive oxygen species (ROS) responsive and antioxidant effects. Network pharmacology indicated that in diabetic wounds, the target genes of PC are mainly enriched in the vascular endothelial growth factor (VEGF)-related pathways, while BAI primarily regulates tyrosine phosphorylation. The complementarity between the two has been validated in both in vitro and in vivo experiments. In summary, the antioxidant drug BAI, identified through high-throughput screening of NPL, could optimize the biological function of PPNs; the newly-synthesized BPPNs may accelerate diabetic wound healing through dual mechanisms of promoting angiogenesis and combating oxidative stress.

Extracellular vesicles (EVs) have shown great promise as drug delivery system (DDS). However, their complex and costly production limit their development for clinical use. Interestingly, the plant kingdom can also produce EV-like nanovesicles that can easily be isolated and purified from a large quantity of raw material at a high yield. In this study, olive-derived nanovesicles (ODNVs) were isolated from raw fruits using serial centrifugations and their physical and biological features characterized to demonstrate their promising potential to be used as a DDS. Nanotracking particle analysis indicated an average size of 109.5 ± 3.0 nm and yield of 10 ODNVs/mL for the purest fraction. Microscopy imaging, membrane fluidity assay and lipidomics analysis showed the presence of a rich lipid bilayer that significantly varied between different sources of ODNVs but showed a distinct signature compared to human EVs. Moreover, ODNVs were enriched in PEN1 and TET8 compared to raw fruits, suggesting an extracellular origin. Interestingly, ODNVs size and yield stayed unchanged after exposure to high temperature (70 °C for 1 h), wide pH range (5-10), and 50-100 nm extrusion, demonstrating high resistance to physical and chemical stresses. This high resistance allowed ODNVs to stay stable in water at 4 °C for a month, or with the addition of 25 mM trehalose for long-term freezing storage. Finally, ODNVs were internalized by both 2D and 3D cell culture without triggering significant cytotoxicity and immunogenicity. Importantly, the anticancer drug doxorubicin (dox) could be loaded by passive incubation within ODNVs and dox-loaded ODNVs decreased cell viability by 90% compared to only 70% for free dox at the same concentration, indicating a higher efficiency of drug delivery by ODNVs. In addition, this high cytotoxicity effect of dox-loaded ODNVs was shown to be stable after a 2-week storage at 4 °C. Together, these findings suggested that ODNVs represent a promising candidate as drug nanocarrier for various DDS clinical applications, as demonstrated by their biocompatibility, high resistance to stress, good stability in harsh environment, and improvement of anticancer drug efficacy.

Developing high-performance nanomedicines to enhance antitumor efficacy remains a hot point in the field of biomedicine. In this study, we designed a versatile nanocomposite (FeS₂@COF-HA/AIPH) integrating covalent organic frameworks (COF) functionalized with pyrite (FeS₂) for synergistic photothermal (PTT), chemodynamic (CDT), thermodynamic (TDT) therapies, and immunotherapy. The superior photothermal effects and catalytic capabilities of FeS₂@COF enabled a minimally invasive PTT/CDT combination. The nanoplatform, with its mesoporous structure, also served as a drug delivery system, encapsulating the thermos-decomposable initiator AIPH. The hyaluronic acid (HA) coating not only improved tumor-targeting efficiency but also prevented nonspecific AIPH release. Under near-infrared (NIR) irradiation, the localized hyperthermia triggered AIPH decomposition, generating toxic alkyl radicals (•R) for TDT, further enhancing CDT efficiency. The combination of PTT, CDT, TDT, and immunotherapy led to potent antitumor effects with minimal systemic toxicity, both in vitro and in vivo. Notably, the nanoplatform effectively reprogrammed tumor-associated macrophages (TAMs) from an M2 to M1 phenotype, boosting antitumor immunity. This multifunctional platform thus offers a promising strategy for integrated PTT, CDT, TDT, and immune activation in tumor therapy.

The regeneration of osteoporotic bone defects remains challenging as the critical stem cell function is impaired by inflammatory microenvironment. Synthetic materials that intrinsically direct osteo-differentiation versus self-renewal of recruited stem cell represent a promising alternative strategy for endogenous bone formation. Therefore, a microenvironmentally optimized polyurethane (PU) /n-HA scaffold to enable sustained delivery of gastrodin is engineered to study its effect on the osteogenic fate of stem cells. It exhibited interconnected porous networks and an elevated sequential gastrodin release pattern to match immune-osteo cascade concurrent with progressive degradation of materials. In a critical-sized femur defect model of osteoporotic rat, 5% gastrodin-PU/n-HA potently promoted neo-bone regeneration by facilitating M2 macrophage polarization and CD146 host stem cell recruitment to defective site. The implantation time-dependently increased the bone marrow mesenchymal stem cell (BMSC) population, and further culture of BMSCs showed a robust ability of proliferation, migration, and mitochondrial resurgence. Of note, some of cell pairs produced one stemness daughter cell while the other committed to osteogenic lineage in an asymmetric cell division (ACD) manner, and a much more compelling ACD response was triggered when 5% gastrodin-PU/n-HA implanted. Further investigation revealed that one-sided concentrated presentation of aPKC and β-catenin in dividing cells effectively induced asymmetric distribution, which polarized aPKC biased the response of the daughter cells to Wnt signal. The asymmetric cell division in skeletal stem cells (SSCs) was mechanically comparable to BMSCs and also governed by distinct aPKC and β-catenin biases. Concomitantly, delayed bone loss adjacent to the implant partly alleviated development of osteoporosis. In conclusion, our findings provide insight into the regulation of macrophage polarization combined with osteogenic commitment of recruited stem cells in an ACD manner, advancing scaffold design strategy for endogenous bone regeneration.

The close spatial and temporal connection between osteogenesis and angiogenesis around type H vasculature is referred as "osteogenesis-angiogenesis coupling", which is one of the basic mechanisms of osteogenesis. Endothelial cells (ECs), bone marrow mesenchymal stem cells (BMSCs), and their specific lineage constitute important cluster that participate in the regulation of osteogenesis and angiogenesis in bone microenvironment. However, the regulatory mechanism of osteogenesis-angiogenesis coupling under the condition of bone healing has not been unveiled. In this study, we demonstrated that the exosome derived from ECs (EC-exo) is an initiator of type H blood vessels formation, and EC-exo acts as a mediator in orchestrating osteogenesis-angiogenesis coupling by enhancing BMSC osteogenic differentiation and EC angiogenesis both in monolayer and stereoscopic co-culture system of primary human cells. The transcriptome array indicated that zinc finger and BTB domain containing 16 (ZBTB16) is a key gene in EC-exo-mediated osteogenesis, and ZBTB16 is indispensable in EC-exo-initiated osteogenesis-angiogenesis coupling. Mechanistically, EC-exo up-regulated the expression of ZBTB16 in BMSCs, thereby promoting osteoprogenitor phenotype transformation; the osteoprogenitors further promote ECs which constitute type H vessel (H-ECs) generation by activating HIF-1α pathway; and the H-ECs conversely promotes osteogenic differentiation of BMSCs. The crosstalk between BMSCs and ECs triggered by EC-exo constitutes a positive feedback loop that enhances osteogenesis-angiogenesis coupling. This study demonstrates that EC-exo can become an effective therapeutic tool to promote bone regeneration and repair.

Cold temperatures have been shown to slow skin wound healing. However, the specific mechanisms underlying cold-induced impairment of wound healing remain unclear. Here, we demonstrate that small extracellular vesicles derived from cold-exposed mouse plasma (CT-sEVs) decelerate re-epithelialization, increase scar width, and weaken angiogenesis. CT-sEVs are enriched with miRNAs involved in the regulation of wound healing-related biological processes. Functional assays revealed that miR-423-3p, enriched in CT-sEVs, acts as a critical mediator in cold-induced impairment of angiogenic responses and poor wound healing by inhibiting phosphatase and poly(A) binding protein cytoplasmic 1 (PABPC1). These findings indicate that cold delays wound healing via miR-423-3p in plasma-derived sEVs through the inhibition of the ERK or AKT phosphorylation pathways. Our results enhance understanding of the molecular mechanisms by which cold exposure delays soft tissue wound healing.

Microfluidic-engineered hydrogel microspheres have emerged as a promising avenue for advancements in tissue engineering and regenerative medicine, particularly through the precise manipulation of fluids to achieve personalized composite biomaterials. In this study, we employed microfluidic technology to fabricate hydrogel microspheres (HMs) using Chinese herbal Bletilla striata polysaccharide (BSP) as the primary material. Concurrently, the natural active ingredient 20(S)-protopanaxadiol (PPD) was encapsulated within the HMs in the form of liposomes (PPD-Lipo), resulting in the formation of nanocomposite hydrogel microspheres (PPD-Lipo@HMs) intended for diabetic wound tissue repair. PPD-Lipo@HMs are characterized by the expansive specific surface area, adjustable mechanical properties, and exceptional biocompatibility. PPD-Lipo@HMs can stimulate the production of vascular endothelial factors, which in turn enhances the migration of endothelial cells, the creation of tubes, angiogenesis, and tissue repair. Moreover, the PPD-Lipo@HMs accumulation produces a microsphere scaffold that effectively covers damaged tissues, promoting the attachment, spread, and multiplication of fibroblast and endothelial cells. The polysaccharide material BSP within PPD-Lipo@HMs can modulate the immune microenvironment of the damaged tissue, reducing inflammation, encouraging re-epithelialization and granulation tissue formation, accelerating angiogenesis and collagen deposition, ultimately leading to tissue repair. The findings highlight the superior therapeutic efficacy of the microfluidic-engineered PPD-Lipo@HMs in addressing the complex challenges of diabetic wound tissue repair, thereby affirming the significant potential of microfluidic engineering technology in tissue repair applications.

Natural products-coordinated metal ions to form the nanomedicines are in the spotlight for cancer therapy. Some natural products could be coordinated with metal ions forming nanomedicines via simple and green environmental self-assembly, which not only improved the bioavailability of natural products, but also conferred multiple therapeutic modalities and multimodal imaging. On the one hand, in the weak acidity, glutathione (GSH) and hydrogen peroxide (HO) overexpression of tumor microenvironment (TME), such carrier-free nanomedicines could be further enhanced the therapeutic effect via optimizing the species of metal ions. On the other hand, nanomedicines could exert the precise treatment of tumor under the guidance of multiple imaging. Hence, this review summarized the research progress in recent years on the application of natural product-coordinated metal ions in cancer therapy. In addition, the prospects and challenges for the application of natural product-coordinated metal ions were discussed, especially how to improve targeting ability and stability and assess the safety of metal ions, so as to facilitate the clinical translation and application of natural product-coordinated metal ions nanomedicines.

Reversing the hypoxic microenvironment of tumors is an important method to enhance the synergistic effect of tumor treatment. In this work, we developed the nanoparticles called Ce6@HGMOF, which consists of a photosensitizer (Ce6), glucose oxidase (GOX), chemotherapy drugs (HCPT) and an iron-based metal-organic framework (MOF). Ce6@HGMOF can consume glucose in tumor cells through "starvation therapy", cut off their nutrition source, and produce gluconic acid and hydrogen peroxide (HO). Utilizing this feature, Ce6@HGMOF can produce oxygen through catalase-like catalytic activity, thereby reversing the hypoxic microenvironment of tumors. This strategy of changing the hypoxic environment can help to slow down the growth of tumor blood vessels and improve the drug-resistant microenvironment to some extent. Meanwhile, increasing the supply of oxygen can enhance the effect of photodynamic therapy (PDT) and enhance the oxidative stress damage caused by reactive oxygen species (ROS) in tumor cells. On the other hand, cancer cells usually produce higher levels of glutathione (GSH) to adapt to high oxidative stress and protect themselves. The Ce6@HGMOF we designed can also consume GSH and induce ferroptosis of tumor cells through Fenton reaction with HO, while enhancing the effect of PDT. This innovative synergistic strategy, the combination of PDT/ferroptosis /starvation therapy, can complement each other and enhance each other. It has great potential as a powerful new anti-tumor paradigm in the future.

Fluorescence nanomaterial sensors have exhibited excellent application potential in biothiols analyses. The fluorescence sensor arrays constructed from upconversion luminescence metal-organic frameworks nanocomposites (LMOFs) can provide impressive discrimination and exquisite fingerprinting capabilities for extremely similar analytes. Herein, an upconversion fluorescence sensor array based on LMOFs featuring UiO-type metal-organic frameworks-functionalized lanthanide-doped upconversion nanoparticles was proposed, wherein Cu can make the fluorescence quenching of LMOFs and preferentially bind biothiols to recover fluorescence in different degrees forming unique fingerprinting. The fluorescence sensor array displayed an excellent pattern recognition for five biothiols (glutathione, homocysteine, N-acetylcysteine, and L/D-cysteine) even at 50 µM by linear discriminant analysis, and the discernment for the enantiomers of L/D-cysteine, as well as the accurate identification (90.0% accuracy) of biothiols in food samples (tea beverage and white wine). Such fluorescence sensor array might provide a simple and efficient detection method for biothiols.

Pulmonary arterial hypertension (PAH) is a severe disease characterized by elevated blood pressure in the pulmonary artery that can ultimately damage the right ventricle of the heart. PAH is pathophysiologically heterogeneous, which makes early diagnosis and treatment difficult. Inflammation is thought to be an important factor in the development and progression of this disease and may explain some of the observed interindividual differences. In the context of both acute and chronic inflammation, neutrophil recruitment to the lung has been suggested as a potential biomarker for studying PAH progression. However, there are currently no specific probes for its non-invasive in vivo detection. The imaging-based gold standard for assessing inflammation is [F] fluorodeoxyglucose (F-FDG), which is not cell specific. This highlights the urgent need for more specific molecular probes to support personalized medicine.

The global demographic shift towards an aging population is generating a rise in neurodegenerative conditions, with Alzheimer's disease (AD) as the most prominent problem. In this landscape, the use of natural supplements has garnered attention for their potential in dementia prevention. Curcumin (Cur), derived from Curcuma longa, has demonstrated promising pharmacological effects against AD by reducing the levels of inflammatory mediators. However, its clinical efficacy is hindered by poor solubility and bioavailability. Our study introduces the use of H-Ferritin nanocages (HFn) as a nanoformulation vehicle for Cur, aiming to enhance its therapeutic potential for AD. In this work, we characterized a nanoformulation of Cur in HFn (HFn-CUR) by evaluating its safety, stability, and its transport across the blood-brain barrier (BBB) in vitro. Moreover, we evaluated the efficacy of HFn-CUR by transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) from both AD patients and healthy controls (HC), and by using the well-established 5xFAD mouse model of AD.

The integration of photoacoustic imaging (PAI) and photothermal therapy (PTT) within the second near-infrared (NIR-II) window, offering a combination of high-resolution imaging and precise non-invasive thermal ablation, presents an attractive opportunity for cancer treatment. Despite the significant promise, the development of this noninvasive phototheranostic nanomedicines encounters challenges that stem from tumor thermotolerance and limited therapeutic efficacy. In this contribution, we designed an amphiphilic semiconducting polymer brush (SPB) featuring a thermosensitive carbon monoxide (CO) donor (TDF-CO) for NIR-II PAI-assisted gas-augmented deep-tissue tumor PTT. TDF-CO nanoparticles (NPs) exhibited a powerful photothermal conversion efficiency (43.1%) and the capacity to trigger CO release after NIR-II photoirradiation. Notably, the liberated CO not only acts on mitochondria, leading to mitochondrial dysfunction and promoting cellular apoptosis but also hinders the overexpression of heat shock proteins (HSPs), enhancing the tumor's thermosensitivity to PTT. This dual action accelerates cellular thermal ablation, achieving a gas-augmented synergistic therapeutic effect in cancer treatment. Intravenous administration of TDF-CO NPs in 4T1 tumor-bearing mice demonstrated bright PAI signals and remarkable tumor ablation under 1064 nm laser irradiation, underscoring the potential of CO-mediated photothermal/gas synergistic therapy. We envision this tailor-made multifunctional NIR-II light-triggered SPB provides a feasible approach to amplify the performance of PTT for advancing future cancer phototheranostics.

Messenger RNA (mRNA) vaccines are a key technology in combating existing and emerging infectious diseases. However, improving the immunogenicity and durability of mRNA vaccines remains a challenge. To elicit optimal immune responses, integrating antigen-encoded mRNA and immunostimulatory adjuvants into a single formulation is a promising approach to enhancing the efficacy of mRNA vaccines. Here, we report an adjuvant strategy to enhance the efficacy of mRNA vaccines by co-loading mRNA encoding the antigen (rabies virus glycoprotein, RABV-G) and mRNA encoding IL-7 into lipid nanoparticles, achieving co-delivery to the same antigen-presenting cells. A single immunization with G&IL-7 mRNA vaccine elicited robust humoral immune responses in mice and conferred complete protection against RABV challenge. Notably, the high levels of neutralizing antibody induced by the G&IL-7 mRNA vaccine were maintained for at least 6 months, providing mice with long-term significant and complete protection against RABV. Additionally, IL-7 also enhanced antibody responses against the SARS-CoV-2. These data demonstrate that IL-7 is a potent mRNA vaccine adjuvant that can provide the required immune stimulation in various mRNA vaccine formulations.

Bacterial infections, especially induced by multidrug-resistant pathogens, have become a significant global health concern. In the infected tissues, biofilms not only serve as a source of nutrients but also act as protective barriers that impede antibiotic penetration. Herein, we developed tea polyphenols epigallocatechin gallate (EGCG) Au nanoparticles (E-Au NPs) through direct one-step self-assembly methods by EGCG chelating with Au ions to eradicate antibiotic-resistant bacteria methicillin-resistant Staphylococcus aureus (MRSA) and prevent the formation of biofilm under near-infrared (NIR) irradiation. The outstanding antibacterial effect involved in mild photothermal therapy, reactive oxygen species production, pathogenicity-related genes regulation, and quinoprotein formation that were specific to the polyphenol-based NPs. The excellent antibacterial and anti-inflammatory therapeutic efficacy of E-Au NPs was validated and topically applied in murine MRSA-infected skin wounds and keratitis model in vivo to kill bacteria, reduce the inflammation response and promote wound healing. Furthermore, the ophthalmic and systemic biosafety profiles were thoroughly evaluated while no significant side effects were revealed achieving a balance between high-efficiency antibacterial properties and biocompatibility. This study provides an effective therapeutic agent of metal-phenolic materials for superficial tissue infection with favorable prognosis and potential in clinical translation.

Bacterial biofilms are one of the major contributors to the refractoriness of septic arthritis. Although nitric oxide (NO)-enhanced photodynamic (PDT) therapy has been involved in biofilm eradication, the anti-biofilm efficacy is usually hindered by the short half-life and limited diffusion distance of active molecules. Herein, we report a three-arm structure using the photosensitive core chlorin e6 to integrate three α-cyclodextrin (α-CD) polyrotaxane chains as the supramolecular nanocarrier of NO-enhanced PDT therapy, in which NO was loaded on the cationic rings (α-CDs). Beneficial from the enhanced permeability of the nanocarrier due to the collective act on biofilms by the molecular motions (slide and rotation of rings) of three chains in different directions, NO capable of inducing biofilm dispersal and reactive oxygen species were efficiently delivered deep inside biofilms under 660 nm laser irradiation, and reactive nitrogen species with stronger bactericidal ability was produced in-situ, further accomplishing bacteria elimination inside biofilms. In-vivo therapeutic performance of this platform was demonstrated in a rat septic arthritis model by eliminating the methicillin-resistant Staphylococcus aureus infection, and potentiating the immune microenvironment regulation and bone loss inhibition, also providing a promising strategy to numerous obstinate clinical infections caused by biofilms.