Methicillin-resistant Staphylococcus aureus (MRSA) infections represent a severe global clinical threat due to its multi-antibiotic resistance, abundant virulence factors, and complex pathogenic mechanisms. In the present study, hollow copper sulfide (CuS) nanoparticles (NPs) with a strong photothermal effect were employed as carriers for the loading of the NO-releasing bioactive molecule S-nitrosoglycine (GSNO). These NPs were also camouflaged with mouse red blood cell membranes (RBCMs) via extrusion to fabricate CuS-GSNO@RBCM NPs designed to effectively eliminate MRSA and its biofilms. Under 1064 nm near-infrared laser irradiation, CuS NPs had a mild photothermal effect, establishing an in situ catalytic platform that boosted reactive oxygen species (ROS) production. In the acidic infectious microenvironment, the release of copper ions induced GSNO to produce NO for reactive nitrogen species (RNS) generation. The ROS and RNS generated in situ by this system consumed endogenous MRSA glutathione, disrupting redox homeostasis, with the additional presence of copper ion-mediated copper death forming a multi-bactericidal network. The RBCMs also neutralized proteins secreted by MRSA to reduce lung cell injury. In vitro and in vivo experiments were employed to verify the MRSA-elimination efficacy of the proposed system, which offers an innovative nanotherapeutic strategy for the precise treatment of drug-resistant bacterial infections.

Immunogenic cell death (ICD) plays a critical role in regulating the immunogenicity of cancer cells to activate the immune response, thus influencing the control of tumor growth. The continuous accumulation of ROS and activation of the endoplasmic reticulum stress (ERS) pathway are both vital for the amplification of ICD effects. Inhibition of the IRE1α-XBP1 signal is considered to facilitate the reduction of the adaptive response of the ER, which exacerbates ERS. Herein, a multifunctional nanoparticle (FE/IR780-NP) composed of XBP1 inhibitor-loaded mesoporous nanoparticles coated with photosensitizer-β-cyclodextrin complexes via GSH-responsive linkers was constructed and characterized. The results of in vitro cellular assays indicate that under intracellular conditions, after the shearing of GSH, the FE/IR780-NPs are divided into peptide-modified Toy-loaded mesoporous silica nanoparticles targeting the ER and IR780-β-cyclodextrin complexes targeting the mitochondrion. The combination of NIR irradiation and XBP1 inhibition significantly potentiates ER stress and amplifies the effects of ICD. Enhanced calreticulin (CRT) exposure, the main indicator of ICD effects, was almost double that of the groups without NIR irradiation (approximately 4 times higher than that of the single toy-treated groups). By establishing a 4T1 triple-negative breast cancer model in mice, the enhanced suppression of tumor growth by FE/IR780-NP-mediated photoimmunotherapy was also supported by in vivo results. FE/IR780-NPs can serve as promising candidates for the amplification of ICD effects to control the progression of aggressive cancers.

Designing multifunctional nanotherapeutic platforms that integrate multiple therapeutic capabilities with enhanced tumor specificity and low systemic toxicity has emerged as a promising strategy for cancer therapy. Herein, we put forward a simple and clear route to construct multifunctional nanoparticles (NPs) integrating chemodynamic therapy (CDT), starvation therapy (ST), and photothermal therapy (PTT) by using polydopamine as a protective layer to coat Cu2+-doped zinc phosphate loaded with glucose oxidase (designated as Cu-ZnP@GOx/PDA/PEG NPs) for optimizing therapeutic efficacy. The obtained Cu-ZnP@GOx/PDA/PEG NPs utilize porous Cu2+-doped ZnP to provide sufficient space for efficient GOx loading, while the PDA shell coated on the surface acts as a "gatekeeper" to prevent enzyme leakage and provides photothermal conversion capabilities. When Cu-ZnP@GOx/PDA/PEG NPs accumulate at tumor sites, the slightly acidic tumor microenvironment triggers the degradation of Cu-ZnP@GOx/PDA/PEG NPs, thereby releasing loaded GOx and doped Cu2+. The released Cu2+ is reduced to Cu+ by glutathione (GSH), subsequently catalyzing H2O2 decomposition to generate highly cytotoxic hydroxyl radicals (•OH) for effective CDT. The released GOx can cut off glucose metabolism in tumor cells to realize ST, and the substances produced during the process of glucose oxidation can improve the microenvironment for better CDT. Under near-infrared irradiation, the generated heat by the photothermal effect of PDA can not only be applied for PTT but also enhance the catalytic efficiency of Fenton-like reactions and the enzymatic activity of GOx, achieving the goal of trimodal synergistic therapy of CDT/ST/PTT. Importantly, in vivo studies using tumor-bearing mice demonstrate that the combined therapy via Cu-ZnP@GOx/PDA/PEG NPs effectively suppresses tumor growth, and no obvious systemic toxicity can be observed. Taken together, the construction of Cu-ZnP@GOx/PDA/PEG NPs can provide a feasible strategy for a safe and efficient cancer therapy.

Introduction: Multidrug-resistant (MDR) bacteria, particularly methicillin-resistant Staphylococcus aureus (MRSA), impede wound infection treatment. Novel strategies shall be designed to effectively eliminate bacteria and facilitate wound recovery. Methods: This study fabricated a new chitosan-based sponge, CS-AuNCs/ICG, to combat MDR bacteria and treat skin wounds. In the CS sponge system, ICG can rapidly generate reactive oxygen species (ROS) upon light irradiation, thereby exerting a rapid bactericidal effect; in contrast, the gold nanoclusters (AuNCs) slowly released from the system can achieve a long-lasting bactericidal effect. Results: In vitro, CS-AuNCs/ICG exhibited excellent antibacterial activity against both planktonic MRSA and biofilm. Moreover, this sponge featured not only an efficient hemostatic property but also a high-porosity porous structure ideal for wound exudate absorption. Local remedy of MRSA-infected mice using the CS-AuNCs/ICG sponge combined with light irradiation resulted in prompt bacterial elimination and prolonged bacteriostasis in the skin wounds, which accelerated wound healing without any observed side effects. Discussion: In summary, the CS-AuNCs/ICG sponge possesses both high-efficiency antibacterial activity and sustained bacterial inhibition ability, demonstrating significant application potential in treating wounds infected with drug-resistant bacteria.

This study investigated the catalytic and non-catalytic transformation of methane over Fe2O3/Al2O3 oxygen carriers under oxygen-carrier-aided combustion (OCAC)-relevant conditions. A novel thermogravimetric tubular-flow fixed-bed reactor (TG-TFBR) is developed to simultaneously monitor solid weight changes and exhaust gas composition, enabling determination of intrinsic reaction kinetics with minimized external mass transfer limitations. The intrinsic kinetic parameters are determined by coupling a 0-D single-particle random pore model with a 1-D packed-bed reactor model, and the Arrhenius relationship is used to correlate rate constants with temperature. Redox experiments reveal distinct two-stage reduction behavior of Fe2O3 at 800–900 °C, with almost complete conversion to Fe3O4 in Stage 1 and complete reduction to FeO only at 900 °C by the end of Stage 2. At 700 and 750 °C, only a single stage is observed and leads to partial reduction to Fe3O4, indicating a hindered Fe3+ → Fe2+ reduction and weakened oxygen-release capacity at lower temperatures. Catalytic oxidation experiments demonstrated that increasing temperature and oxygen concentration significantly enhanced CH4 conversion and CO2 yield. Compared with homogeneous reactions, Fe2O3/Al2O3 oxygen carriers exhibit clear catalytic promotion, with exhibiting a lower activation energy and higher rate constant. Overall, the findings elucidate the dual catalytic and oxygen-carrier roles of Fe2O3 in methane transformation under OCAC-relevant conditions. It supports more accurate modeling of OCAC processes and helps guide operating strategies to enhance fuel utilization.

Amino acid (AA)-based nanoparticles (NPs) hold promise in cancer therapy due to their excellent biocompatibility and the various therapeutic functions derived from AA monomers. Here, we developed a universal one-step method to synthesize AA-based NPs. We then constructed L-Arginine (L-Arg)/calcium phosphate (CaP) NPs to enhance cancer therapy through synergistic calcium overload to induce apoptosis and immunogenic cell death. The engineered L-Arg/CaP NPs rapidly degraded and released a large amount of exogenous calcium ions (Ca2+) in the acidic tumor microenvironment (TME). Notably, L-Arg-derived NO synergistically enhanced calcium overload through two distinct mechanisms: (1) induction of S-nitrosylation of the ryanodine receptor (RyR) on the endoplasmic reticulum (ER) to facilitate endogenous Ca2+ release, and (2) significant downregulation of plasma membrane Ca2+-ATPase (PMCA) expression to inhibit Ca2+ efflux. This unique three-level regulatory mechanism involving external Ca2+ supply, internal Ca2+ release, and efflux inhibition created a cascading amplification of intracellular Ca2+ concentration. Importantly, it overcame the limitations of tumor cell stress adaptation in conventional single-ion therapy, thereby establishing a new therapeutic paradigm. In vitro and in vivo studies confirmed that L-Arg/CaP NPs induce tumor suppression with excellent biosafety, indicating the potential for an innovative strategy integrating calcium overload and gas therapy for cancer treatment.

The oral administration of drugs for cancer therapy can maintain optimal blood concentrations, is biologically safe and simple, and is preferred by many patients. However, the complex lumen environment, mucus layer, and intestinal epithelial cells are biological barriers that hinder the absorption of orally administered drugs. In this study, sea urchin-like manganese-doped copper selenide nanoparticles (Mn-Cu2-xSe NPs) were designed using an anion exchange method and coated with calcium alginate and chitosan (AC) to form Mn-Cu2-xSe@AC capsules. The pH-responsive swelling behavior of the AC protective layer aided doxorubicin (DOX)-loaded Mn-Cu2-xSe NPs in overcoming multiple biological barriers, maintained their stability in gastric acid, and facilitated the release of the NPs in the small intestine. The intestinal epithelial cell permeability of DOX/Mn-Cu2-xSe NPs was confirmed using a monolayer absorption model involving Caco-2 human epithelial cells. The released DOX/Mn-Cu2-xSe NPs smoothly passed through the mucus layer, and were absorbed by intestinal epithelial cells. In mice, the NPs circulated in the blood and passively targeted the tumors through blood circulation by enhancing the permeability and retention effect to achieve significant tumor suppression and reduce damage to normal tissues. In addition, the unique sea urchin-like morphology of Mn-Cu2-xSe NPs enhanced the absorption in the near-infrared-II (NIR-II) window for photothermal therapy, realized the near-infrared-stimulated response release of DOX for increased chemotherapy, and promoted the Fenton-like effect because of the doping of manganese ions for chemodynamic therapy. These effects could permit the development of various synergistic cancer treatments. The use of DOX/Mn-Cu2-xSe@AC capsules as a multistage oral drug delivery system may overcome the sequential absorption barriers that currently hinder chemotherapy, chemodynamic, and photothermal therapies.

Staphylococcus aureus (S. aureus) is recognized as among the most critical bacterial pathogens globally. A significant portion of the complications associated with S. aureus infections arises from its ability to persist inside host phagocytes, particularly macrophages, making the eradication of intracellular S. aureus vital for therapeutic success. Regrettably, many antibiotics exhibit limited penetration into cells, underscoring the necessity for efficient intracellular delivery mechanisms. In this study, vancomycin-loaded chitooligosaccharide nanoparticles (COS@Van) coated with hyaluronic acid (HA), were engineered to function as an active-targeting antibiotic carrier recorded as HA/COS@Van. The HA coating serves as an external shell, which 1) covers the positive surface charge of COS NPs, thereby enhancing their biocompatibility and extending circulation time, and 2) facilitates targeted delivery to macrophages through specific interactions with the CD44 receptor. Confocal laser scanning microscopy (CLSM) and flow cytometry (FCM) experiments confirmed that HA/COS could effectively accumulate in methicillin-resistant S. aureus (MRSA) infected macrophages. Additionally, when administered intravenously in mouse models, HA/COS demonstrated markedly increased accumulation in the liver, the primary location of infected macrophages. These findings highlight the active-targeting capabilities of HA/COS both in vitro and in vivo settings. Consequently, after being loaded with Van, HA/COS@Van exhibited superior efficacy in killing intracellular MRSA in vitro, as compared to free Van. Furthermore, HA/COS@Van also demonstrated enhanced bactericidal activity in both mouse acute peritonitis model and mouse organ infection model. Therefore, this active-targeting delivery system may hold promise in advancing therapeutic outcomes for infections related to intracellular pathogens.

Portal vein tumor thrombus (PVTT) is a poor prognostic factor for hepatocellular carcinoma (HCC) patients, highlighting the need for an oral drug delivery system that combines convenience, simplicity, biosafety, and improved patient compliance. Leveraging the unique anatomy of the portal vein and insights from single-cell RNA sequencing of the PVTT tumor microenvironment, we developed oral pellets using CaCO3@PDA nanoparticles (NPs) encapsulating both doxorubicin hydrochloride and low molecular weight heparin. These NPs target the tumor thrombus microenvironment, aiming to break down the thrombus barrier and turn the challenge of portal vein blockage into an advantage by enhancing drug delivery efficiency through oral administration. The NPs-based oral delivery system achieved excellent antitumor effects with minimal side effects, demonstrating a promising strategy for managing PVTT in advanced HCC and addressing tumor types associated with vascular invasion and hypercoagulability.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major threat to human health due to its multi-antibiotic resistance, either intrinsic or acquired. One of the acquired mechanisms lies in MRSA biofilms, which shield bacteria from antibiotic eradication, contributing to chronic infections. To address this challenge, we constructed the novel non-antibiotic nano-delivery platforms based on copper sulfide/gold nanocluster@liposomes nanoparticles (CuS/AuNCs@Lip NPs). Upon the excitation of 1064 nm near-infrared light, these NPs exhibit excellent photothermal effect and reactive oxygen species (ROS) generation ability, destroying the structure of bacterial membrane to kill MRSA and removing biofilm effectively. In vivo experiments demonstrated the target enrichment at infection sites, significant therapeutic efficacy in the subcutaneous cyst and pneumonia models caused by MRSA in mice, and a favorable biosafety profile. This study provides novel non-antibiotic strategies for treating drug-resistant bacterial infections that combine efficient antimicrobial properties with biosafety.

The effective treatment of infections induced by biofilms has remained a substantial challenge in clinical practice. Presently, there is an imperative demand for innovative antimicrobial strategies that can not only eliminate biofilms but also incorporate controlled delivery and intelligent release mechanisms. In this research, the charge-reversible nonantibiotic nanodelivery system (MPDA/AuNCs/ICG@Lip NPs) is synthesized. Initially, AuNCs and indocyanine green (ICG) were introduced onto MPDA NPs via adsorption and mesoporous loading, followed by the modification of the phospholipids on the exterior surface. Within the biofilm microenvironment, the surface charge was reversed, thereby improving its affinity for methicillin-resistant Staphylococcus aureus (MRSA) and facilitating enhanced biofilm permeability. Owing to the ultrasmall AuNCs, they were internalized by the bacteria and, in conjunction with ICG, contributed to the elevation of local ROS concentrations under the 808 nm laser. As anticipated, the in vitro findings confirmed that MPDA/AuNCs/ICG@Lip NPs demonstrated superior biofilm-clearing capabilities and antibacterial effect. In vivo experiments corroborated that MPDA/AuNCs/ICG@Lip NPs successfully targeted the cyst site and remained localized for an extended period, resulting in excellent therapeutic efficacy. This discovery offers a novel perspective for the development of nonantibiotic nanoplatform for clearing MRSA.

Tumor immunotherapy has garnered significant attention, however, several notable challenges remain to be addressed, including: 1) enhancing active targeting, 2) effectively shielding immune checkpoints, and 3) inducing the transformation of "cold" tumor into "hot". In this study, an "all-in-one" extracellular anaerobic bacterial nanocomposite system is constructed. Escherichia coli Nissle 1917 (EcN) is enveloped with polydopamine via self-polymerization (PDAEcN), subsequently conjugated with a chitosan oligosaccharide (COS) nanoparticle immunostimulant backpack, denoted as PDAEcN/COS. The PDA coating is capable of concealing EcN polysaccharides, masking the immunogenic bacterial surface antigens, and inducing a mild photothermal therapy (PTT) effect. Moreover, PDAEcN/COS exhibits targeted accumulation in hypoxic regions of solid tumors and demonstrates pronounced enrichment on tumor cell surfaces, attributed to the bacterial hypoxic region targeting ability and adhesive properties of PDA, physically obstructing the immune checkpoint. Simultaneously, both EcN and COS markedly enhanced the transformation of M2 macrophages into the M1 phenotype, whereas mild PTT-induced immunogenic cell death (ICD) further mitigated the immunosuppressive nature of the hypoxic tumor microenvironments (TMEs). This integrated therapeutic approach eradicated tumors without eliciting metastasis or discernible side effects following a single injection and laser irradiation in a murine 4T1 cancer model. Ultimately, the immunostimulatory capacity of PDAEcN/COS is considered to hold significant potential for developing novel and efficacious therapies for immunologically "cold" triple-negative breast cancer (TNBC).

Methicillin-resistant Staphylococcus aureus (MRSA), whose resistance is primarily due to its biochemical resistance mechanisms, its ability to form protective biofilms, and its ability to evade clearance by macrophages. Photodynamic therapy (PDT) was an alternative treatment strategy against MRSA infection, but was restricted by hypoxia. Here, a photodynamic O2 self-supplying bacterial microenvironment-responsive (BME) calcium peroxides nanocomposite (CaO2@HA/pllCe6) was constructed for MRSA treatment. CaO2@HA/pllCe6 was prepared by a two-step procedure. Firstly, hyaluronic acid-modified calcium peroxide nanocomposites (CaO2@HA) were synthesized in a one-step process. Then, as-prepared positively charged poly-L-lysine (pllCe6) with enhanced photocatalytic activity was bound to the surface of CaO2@HA through electrostatic interaction. In this design, the CaO2@HA/pllCe6 was speculated to accumulate at the infection site due to the EPR effect and macrophage targeting. Moreover, the positive charged pllCe6 and HA corona on the surface could facilitate bacterial adhesion, biofilm penetration and macrophage-specific uptake. After initial interaction, plenty of H2O2 and O2 could be simultaneously released in acid and hyaluronidase overexpressed BME for hypoxia relief and ROS generation, leading to enhanced photodynamic therapy. Moreover, the generated ROS and released Ca2+could polarize macrophages into classically activated (M1) phenotypes, thereby enhancing antimicrobial immunity. Satisfactory anti-bacterial effects of CaO2@HA/pllCe6 against planktonic bacteria, biofilm bacteria and intracellular bacteria, along with the photodynamic immunomodulatory synergistic effects, were verified both in vitro and in vivo, with good biocompatibility in the latter. As a proof-of-concept, this research provided an innovative strategy which could enhance the effects of photodynamic therapy while activating macrophages, hold promise in the fight against MRSA-associated infections.

Rheumatoid arthritis (RA) is a prevalent chronic autoimmune disorder characterized by joint pain and progressive damage that can severely impair daily activities and reduce overall quality of life. The long-term, high-dose administration of conventional drugs often results in severe adverse effects. In this study, we designed a multifunctional nanoplatform for synergetic chemo-photothermal therapy (chemo-PTT) of RA. Au nanoflowers (AuNFs) were prepared using the l-ascorbic acid reduction method, and the surface of AuNFs was modified with FA-SH and SH-β-CD through gold-sulfur bonds. Consequently, dexamethasone (DEX)-loaded FA-AuNFs-CD was constructed (designed as FA-AuNFs-CD/DEX). Lipopolysaccharide (LPS) was used to stimulate an inflammatory response, and DEX-loaded AuNFs were evaluated for their anti-inflammatory effects using a RAW264.7 cell inflammatory model. An adjuvant arthritis rat model was established to observe the anti-RA effect of FA-AuNFs-CD/DEX under 808 nm near-infrared (NIR) laser irradiation. In vivo and in vitro evaluations revealed that the combined chemo-PTT effectively eliminated enriched inflammatory cells in the joint cavity and significantly reduced the production of many inflammatory cytokines, demonstrating promising anti-RA effects in the adjuvant-induced arthritis (AIA) rat model. In conclusion, the combination of chemo-PTT offers a potential new therapeutic strategy for RA treatment.

Introduction:Pseudomonas aeruginosa (P. aeruginosa)-induced pneumonia is marked by considerable infiltration of inflammatory cells and biofilm formation, which causes acute and transient lung inflammation and infection. Nevertheless, the discovery of alternative preventative and therapeutic methods is essential due to the high mortality rates in clinical settings and the resistance of P. aeruginosa infection to multiple medications. Purpose:In this research, we constructed amphiphilic Janus nanoparticles (JNPs, denoted as SSK1@PDA/CaP@CIP), loaded with hydrophobic SSK1, a β-galactosidase (β-gal)-activated prodrug for reducing macrophages, and hydrophilic ciprofloxacin (CIP), a classic antibiotic for treating infection. SSK1@PDA/CaP@CIP was designed to effectively attenuate inflammation, eradicate biofilms, and combat planktonic P. aeruginosa. Results:As expected, SSK1@PDA/CaP@CIP was able to target the infection site and demonstrated outstanding efficacy in treating P. aeruginosa strain PAO1-induced pneumonia by regulating macrophage infiltration to reduce inflammation and removing planktonic bacteria and biofilms to control infection. Additionally, the primary organs did not exhibit any discernible pathological changes following treatment with SSK1@PDA/CaP@CIP, which indicates superior biocompatibility throughout the treatment course. Discussion:In conclusion, our investigation introduced a promising approach to the treatment of pneumonia associated with PAO1.

We developed a new method to synthesize polyethylene glycol modified ultra small iron embedded in mesoporous carbon nanoparticle (C/Fe-PEG NP) for hydrogen (H2) assisted photothermal synergistic therapy. Herein, we use a simple in-situ reduction method to obtain the C/Fe NP in one-step carbonizing process, which is further modified by the biocompatible polyethylene glycol (PEG) on the surface of C/Fe NP to acquire high stability in physiological solutions. Utilizing the excellent photothermal property from the mesoporous carbon and the controllable H2 release property in the weakly acidic tumor microenvironment by the ultra-small Fe, the obtained C/Fe-PEG NPs can effective kill the cancer cells, meanwhile, protect normal cells without drugs. This selective anti-cancer mechanism of C/Fe-PEG NPs may because the produced H2 selective change the mitochondrial energy metabolism. In vivo results prove that the C/Fe-PEG NPs achieve excellent tumor ablation therapeutic effect and normal tissue protecting ability benefit from the H2-assisted photothermal therapy, promising the use of novel nanomaterials with more safety method for future cancer therapy.

Background:With the rapid development of nanotechnology, constructing a multifunctional nanoplatform that can deliver various therapeutic agents in different departments and respond to endogenous/exogenous stimuli for multimodal synergistic cancer therapy remains a major challenge to address the inherent limitations of chemotherapy. Methods:Herein, we synthesized hollow mesoporous Prussian Blue@zinc phosphate nanoparticles to load glucose oxidase (GOx) and DOX (designed as HMPB-GOx@ZnP-DOX NPs) in the non-identical pore structures of their HMPB core and ZnP shell, respectively, for photothermally augmented chemo-starvation therapy. Results:The ZnP shell coated on the HMPB core, in addition to providing space to load DOX for chemotherapy, could also serve as a gatekeeper to protect GOx from premature leakage and inactivation before reaching the tumor site because of its degradation characteristics under mild acidic conditions. Moreover, the loaded GOx can initiate starvation therapy by catalyzing glucose oxidation while causing an upgradation of acidity and H2O2 levels, which can also be used as forceful endogenous stimuli to trigger smart delivery systems for therapeutic applications. The decrease in pH can improve the pH-sensitivity of drug release, and O2 can be supplied by decomposing H2O2 through the catalase-like activity of HMPBs, which is beneficial for relieving the adverse conditions of anti-tumor activity. In addition, the inner HMPB also acts as a photothermal agent for photothermal therapy and the generated hyperthermia upon laser irradiation can serve as an external stimulus to further promote drug release and enzymatic activities of GOx, thereby enabling a synergetic photothermally enhanced chemo-starvation therapy effect. Importantly, these results indicate that HMPB-GOx@ZnP-DOX NPs can effectively inhibit tumor growth by 80.31% and exhibit no obvious systemic toxicity in mice. Conclusion:HMPB-GOx@ZnP-DOX NPs can be employed as potential theranostic agents that incorporate multiple therapeutic modes to efficiently inhibit tumors.

Methicillin-resistant Staphylococcus aureus (MRSA) within cells proves exceptionally challenging to eradicate using conventional antimicrobials, resulting in recurring infections and heightened resistance. Herein, we reported an innovative mannosylated lipid-coated photodynamic/photothermal calcium phosphate nanoparticle (MAN-LCaP@ICG) for eradicating intracellular MRSA. The MAN-LCaP functioned as the vehicle for drug delivery, exhibiting preferential uptake by macrophages and facilitating the transport of ICG to intracellular pathogens. The MAN units integrated into MAN-LCaP@ICG could promote binding with MAN residuals on macrophage cells, as evidenced by cellular uptake assays using fluorescence microscopy and flow cytometry. Following its targeted accumulation, MAN-LCaP@ICG could enter into the cytoplasm and efficiently eradicate intracellular MRSA by a combination of the lysosome escape capability of CaP and the photodynamic and photothermal therapeutic effects of ICG. Furthermore, MAN-LCaP@ICG could kill MRSA more effectively than LCaP@ICG without MAN units or free ICG in a mouse peritoneal infection model. Therefore, MAN-LCaP@ICG provided a promising direction for human clinical application in combating intracellular infections.

In this study, Janus nanoparticles, Ce6–PDA/CaP–GSNO, were constructed to effectively eradicate biofilms and combat methicillin-resistant Staphylococcus aureus (MRSA) infections through nitric oxide (NO) synergistic photodynamic therapy.

Methicillin-resistant Staphylococcus aureus (MRSA), recognized for its resistance, poses a formidable challenge to public health, primarily attributable to its biochemical resistant mechanisms, capacity to form protective biofilms, and capacity to evade macrophage surveillance. In response to this threat, we constructed a multifunctional pH-responsive dimeric prodrug based on mannose (MAN) and cinnamaldehyde (CMA). This prodrug, designated as MACA@indocyanine green (ICG), incorporates the photosensitizer ICG. The nanoscale properties and MAN units integrated into the MACA@ICG prodrug could promote effective binding with infectious microbes or MAN residues on mammalian cells. This specific interaction, corroborated by co-localization studies using confocal microscopy and flow cytometry, is crucial for initial bacterial binding, biofilm penetration, and macrophage-specific uptake, all of which are strategic in surmounting the biological barriers posed by MRSA. Following its targeted accumulation, MACA@ICG was demonstrated responsiveness to the acidic microenvironment of bacteria to release free CMA, a natural compound with antimicrobial properties. The drug release, synergistically coupled with the effects of photothermal therapy (PTT) and photodynamic therapy (PDT) showcased superior synergistic antibacterial efficacy both in vitro and in vivo. Therefore, MACA@ICG was verified remarkable capabilities in surmounting bacterial biological barriers and exceptional antibacterial efficiency through the combinational treatments of herbal components, PDT and PTT.