Engineering lauric acid-based nanodrug delivery systems for restoring chemosensitivity and improving biocompatibility of 5-FU and OxPt against Fn-associated colorectal tumor.

Colorectal cancer (CRC) occurs in the colorectum and ranks second in the global incidence of all cancers, accounting for one of the highest mortalities. Although the combination chemotherapy regimen of 5-fluorouracil (5-FU) and platinum(IV) oxaliplatin prodrug (OxPt) is an effective strategy for CRC treatment in clinical practice, chemotherapy resistance caused by tumor-resided Fusobacterium nucleatum (Fn) could result in treatment failure. To enhance the efficacy and improve the biocompatibility of combination chemotherapy, we developed an antibacterial-based nanodrug delivery system for Fn-associated CRC treatment. A tumor microenvironment-activated nanomedicine 5-FU-LA@PPL was constructed by the self-assembly of chemotherapeutic drug derivatives 5-FU-LA and polymeric drug carrier PPL. PPL is prepared by conjugating lauric acid (LA) and OxPt to hyperbranched polyglycidyl ether. In principle, LA is used to selectively combat Fn, inhibit autophagy in CRC cells, restore chemosensitivity of 5-FU as well as OxPt, and consequently enhance the combination chemotherapy effects for Fn-associated drug-resistant colorectal tumor. Both in vitro and in vivo studies exhibited that the tailored nanomedicine possessed efficient antibacterial and anti-tumor activities with improved biocompatibility and reduced non-specific toxicity. Hence, this novel anti-tumor strategy has great potential in the combination chemotherapy of CRC, which suggests a clinically relevant valuable option for bacteria-associated drug-resistant cancers.

Amphiphilic polymeric nanodrug integrated with superparamagnetic iron oxide nanoparticles for synergistic antibacterial and antitumor therapy of colorectal cancer.

Colorectal cancer (CRC) is one of the most prevalent and deadly malignancies that can be influenced by Fusobacterium nucleatum (Fn), a bacterium that promotes tumor development and chemoresistance, resulting in limited therapeutic efficacy. Traditional antibiotics cannot effectively eliminate Fn at tumor site due to issues like biofilm formation, while chemotherapy alone fails to suppress tumor progression. Therefore, the development of new methods to eliminate Fn and promote antitumor efficacy is of great significance for improving the outcome of CRC treatment. Herein, we developed a nanodrug (OPPL) that integrates oleic acid-modified superparamagnetic iron oxide nanoparticles (O-SPIONs) and an amphiphilic polymer (PPL) to deliver the platinum prodrug and antimicrobial lauric acid (LA) for enhancing the treatment of CRC. We demonstrated that OPPL can synergistically enhance antibacterial and biofilm disruption activities against Fn along with the antimicrobial LA by producing reactive oxygen species (ROS) through its peroxidase-like activity. Furthermore, the OPPL nanodrug can increase intracellular ROS, promote lipid peroxides and deplete glutathione, leading to ferroptosis. By combining chemotherapy and induced ferroptosis, the OPPL nanodrug exhibited high cytotoxicity against CRC cells. In vivo studies showed that the OPPL nanodrug could enhance tumor accumulation, enable magnetic resonance imaging, suppresse tumor growth, and inhibit growth of intratumor Fn. These results suggest that OPPL is an effective and promising candidate for the treatment of Fn-infected CRC. STATEMENT OF SIGNIFICANCE: The enrichment of Fusobacterium nucleatum (Fn) in colorectal cancer is reported to exacerbate tumor malignancy and is particularly responsible for chemoresistance. To this respect, we strategically elaborated multifaceted therapeutics, namely OPPL nanodrug, combining oleic acid-modified superparamagnetic iron oxide nanoparticles (O-SPIONs) with a polymer containing a platinum prodrug and antimicrobial lauric acid. The O-SPION components exert distinctive peroxidase-like activity, capable of stimulating Fenton reactions selectively in the tumor microenvironment, consequently accounting for the progressive production of reactive oxygen species. Hence, O-SPIONs have been demonstrated to not only supplement the antimicrobial activities of lauric acid in overcoming Fn-induced chemoresistance but also stimulate potent tumor ferroptosis. Our proposed dual antimicrobial and chemotherapeutic nanodrug provides an appreciable strategy for managing challenging Fn-infected colorectal cancer.

Remotely Controllable Supramolecular Nanomedicine for Drug-Resistant Colorectal Cancer Therapy Caused by Fusobacterium nucleatum.

Fusobacterium nucleatum (Fn) existing in the community of colorectal cancer (CRC) promotes CRC progression and causes chemotherapy resistance. Despite great efforts that have been made to overcome Fn-induced chemotherapy resistance by co-delivering antibacterial agents and chemotherapeutic drugs, increasing the drug-loading capacity and enabling controlled release of drugs remain challenging. In this study, a novel supramolecular upconversion nanoparticle (SUNP) is constructed by incorporating a positively charged polymer (PAMAM-LA-CD) with Fn inhibition capacity, a negatively charged platinum (IV) oxaliplatin prodrug (OXA-COOH), upconversion nanoparticle (UCNPs) and polyethylene glycol-azobenzene (PEG-Azo) to enhance drug-loading and enable on-demand drug release for drug-resistant CRC treatment. SUNPs exhibit high drug-loading capacity (30.8%) and good structural stability under normal physiological conditions, while disassembled upon exogenous NIR excitation and endogenous azo reductase in the CRC microenvironment to trigger drug release. In vitro and in vivo studies demonstrate that SUNPs presented good biocompatibility and robust performance to overcome chemoresistance, thereby significantly inhibiting Fn-infected cancer cell proliferation. This study leverages multiple dynamic chemical designs to integrate both advantages of drug loading and release in a single system, which provides a promising candidate for precision therapy of bacterial-related drug-resistant cancers.

In situ-activated photothermal nanoplatform for on-demand NO gas delivery and enhanced colorectal cancer treatment.

The naturally evolved and intestinal pathogenic Fusobacterium nucleatum (Fn)-induced drug resistance profoundly impaired the efficacy of chemotherapy against colorectal cancer (CRC). Alternative treatment modalities against Fn-associated CRC are desperately needed. Herein, we engineer an in situ-activated anti-tumor and antibacterial nanoplatform (Cu2O/BNN6@MSN-Dex) to allow photoacoustic (PA) imaging-guided photothermal and NO gas combinatorial therapy for enhanced Fn-associated CRC treatment. The nanoplatform is constructed by loading cuprous oxide (Cu2O) and nitric oxide (NO) donor (BNN6) into dextran-decorated mesoporous silica nanoparticles (MSN), which is finally surface-functionalized with dextran via dynamic boronate linkage. Cu2O can be sulfuretted in situ by endogenous hydrogen sulfide overexpressed in CRC to produce copper sulfide with remarkable PA and photothermal properties, enabling the generation of NO from BNN6 under 808 nm laser irradiation, which is eventually triggered to release by multiple biological cues in the tumor microenvironment. Cu2O/BNN6@MSN-Dex exhibits superior biocompatibility, as well as H2S-triggered near-infrared-controlled antibacterial and anti-tumor performance in vitro and in vivo via photothermal and NO gas combination therapy. Furthermore, Cu2O/BNN6@MSN-Dex provokes systemic immune responses, thereby promoting anti-tumor efficacy. This study provides a conbinational strategy to effectively inhibit tumors and intratumor pathogens for enhanced CRC treatment.

An orally delivered bacteria-based coacervate antidote for alcohol detoxification.

Alcohol intoxication causes serious diseases, whereas current treatments are mostly supportive and unable to convert alcohol into nontoxic products in the digestive tract. To address this issue, an oral intestinal-coating coacervate antidote containing acetic acid bacteria (AAB) and sodium alginate (SA) mixture was constructed. After oral administration, SA reduces absorption of ethanol and promotes the proliferation of AAB, and AAB converts ethanol to acetic acid or carbon dioxide and water by two sequential catalytic reactions in the presence of membrane-bound alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). In vivo study shows that the bacteria-based coacervate antidote can significantly reduce the blood alcohol concentration (BAC) and effectively alleviates alcoholic liver injury in mice. Given the convenience and effectiveness of oral administration, AAB/SA can be used as a promising candidate antidote for relieving alcohol-induced acute liver injury.

In Situ Sprayed Biotherapeutic Gel Containing Stable Microbial Communities for Efficient Anti-Infection Treatment.

Systematic administration of antibiotics to treat infections often leads to the rapid evolution and spread of multidrug-resistant bacteria. Here, an in situ-formed biotherapeutic gel that controls multidrug-resistant bacterial infections and accelerates wound healing is reported. This biotherapeutic gel is constructed by incorporating stable microbial communities (kombucha) capable of producing antimicrobial substances and organic acids into thermosensitive Pluronic F127 (polyethylene-polypropylene glycol) solutions. Furthermore, it is found that the stable microbial communities-based biotherapeutic gel possesses a broad antimicrobial spectrum and strong antibacterial effects in diverse pathogenic bacteria-derived xenograft infection models, as well as in patient-derived multidrug-resistant bacterial xenograft infection models. The biotherapeutic gel system considerably outperforms the commercial broad-spectrum antibacterial gel (0.1% polyaminopropyl biguanide) in pathogen removal and infected wound healing. Collectively, this biotherapeutic strategy of exploiting stable symbiotic consortiums to repel pathogens provides a paradigm for developing efficient antibacterial biomaterials and overcomes the failure of antibiotics to treat multidrug-resistant bacterial infections.

Polymeric nano-system for macrophage reprogramming and intracellular MRSA eradication.

Intracellular Methicillin-Resistant Staphylococcus aureus (MRSA) remains a major factor of refractory and recurrent infections, which cannot be well addressed by antibiotic therapy. Here, we design a cellular infectious microenvironment-activatable polymeric nano-system to mediate targeted intracellular drug delivery for macrophage reprogramming and intracellular MRSA eradication. The polymeric nano-system is composed of a ferrocene-decorated polymeric nanovesicle formulated from poly(ferrocenemethyl methacrylate)-block-poly(2-methacryloyloxyethyl phosphorylcholine) (PFMMA-b-PMPC) copolymer with co-encapsulation of clofazimine (CFZ) and interferon-γ (IFN-γ). The cellular-targeting PMPC motifs render specific internalization by macrophages and allow efficient intracellular accumulation. Following the internalization, the ferrocene-derived polymer backbone sequentially undergoes hydrophobic-to-hydrophilic transition, charge reversal and Fe release in response to intracellular hydrogen peroxide over-produced upon infection, eventually triggering endosomal escape and on-site cytosolic drug delivery. The released IFN-γ reverses the immunosuppressive status of infected macrophages by reprogramming anti-inflammatory M2 to pro-inflammatory M1 phenotype. Meanwhile, intracellular Fe2+-mediated Fenton reaction together with antibiotic CFZ contributes to increased intracellular hydroxyl radical (•OH) generation. Ultimately, the nano-system achieves robust potency in ablating intracellular MRSA and antibiotic-tolerant persisters by synchronous immune modulation and efficient •OH killing, providing an innovative train of thought for intracellular MRSA control.

NIR-activated nanosystems with self-modulated bacteria targeting for enhanced biofilm eradication and caries prevention.

The efficacious delivery of antimicrobial drugs to intractable oral biofilms remains a challenge due to inadequate biofilm penetration and lack of pathogen targeting. Herein, we have developed a microenvironment-activated poly(ethylene glycol) (PEG)-sheddable nanoplatform to mediate targeted delivery of drugs into oral biofilms for the efficient prevention of dental caries. The PEGylated nanoplatform with enhanced biofilm penetration is capable of deshielding the PEG layer under slightly acidic conditions in a PEG chain length-dependent manner to re-expose the bacteria-targeting ligands, thereby facilitating targeted codelivery of ciprofloxacin (CIP) and IR780 to the bacteria after accumulation within biofilms. The nanoplatform tends to induce bacterial agglomeration and suffers from degradation in the acidic oral biofilm microenvironment, triggering rapid drug release on demand around bacterial cells. The self-modulating nanoplatform under near-infrared (NIR) irradiation accordingly displays greatly augmented potency in oral biofilm penetration and disruption compared with drugs alone. Topical oral treatment with nanoplatforms involving synergetic pharmacological and photothermal/photodynamic trinary therapy results in robust biofilm dispersion and efficacious suppression of severe tooth decay in rats. This versatile nanoplatform can promote local accumulation and specific drug transport into biofilms and represents a new paradigm for targeted drug delivery for the management of oral biofilm-associated infections.

Harnessing in situ glutathione for effective ROS generation and tumor suppression via nanohybrid-mediated catabolism dynamic therapy.

The overexpression of glutathione (GSH) in cancer cells has long been regarded as the primary obstacle for reactive oxygen species (ROS)-involved anti-tumor therapies. To solve this issue, a ferric ion and selenite-codoped calcium phosphate (Fe/Se-CaP) nanohybrid here is fabricated to catabolize endogenous GSH, instead of directly deleting it, to trigger a ROS storm for tumor suppression. The selenite component in Fe/Se-CaP can catabolize GSH to superoxide anion (O2•-) and hydroxyl radicals (•OH) via cascade catalytic reactions, elevating oxidative stress while destroying antioxidant system. The doped Fe can further catalyze the soaring hydrogen peroxide (H2O2) originated from O2•- to •OH via Fenton reactions. Collectively, Fe/Se-CaP mediated self-augmented catabolism dynamic therapy finally induces apoptosis of cancer cells owing to the significant rise of ROS and, combined with CaP adjuvant, evokes adaptive immune responses to suppress tumor progression, providing an innovative train of thought for ROS-involved anti-tumor therapies.

Polymeric PD-L1 blockade nanoparticles for cancer photothermal-immunotherapy.

Checkpoint inhibitors, such as antibodies blocking the PD-1/PD-L1 pathway, are among the most promising immunotherapies to treat metastatic cancers, but their response rate remains low. In addition, the usage of monoclonal antibodies as checkpoint inhibitors is associated with a series of drawbacks. Herein, an all synthetic nanoparticle with PD-L1 blockade capability is developed for cancer photothermal-immunotherapy. The polymeric nanoparticle integrates photothermal treatment, antitumor vaccination, and PD-1/PD-L1 blockade in a single system to augment the antitumor efficacy. In a CT26 bilateral tumor model, intravenously injected nanoparticles accumulate in tumor sites and mediate strong photothermal effects, eradicate the NIR treated primary tumors and elicit strong antitumor immunity by inducing immunogenic cell death (ICD). Growth of the untreated distant tumors is also suppressed due to the synergies of systemic antitumor immune activation and PD-L1 blockade. Our strategy offers a simple but promising approach for the treatment of metastatic cancer.

A bioinspired hierarchical nanoplatform targeting and responding to intracellular pathogens to eradicate parasitic infections.

Intracellular bacteria-mediated antibiotic tolerance, which acts as a "Trojan horse," plays a critical and underappreciated role in chronic and recurrent infections. Failure of conventional antibiotic therapy is often encountered because infected cells prevent drug permeation or the drug concentration is too low at the site of resident bacteria. New paradigms are therefore urgently needed for intracellular anti-infective therapy. Here, a novel therapeutic was developed for targeted delivery of antibiotics into bacteria-infected macrophages to improve drug accumulation in intracellular niches and bactericidal activity of antibiotics against intracellular pathogens. This hierarchical nanoplatform includes a glycocalyx-mimicking shell that enables rapid uptake by macrophages. Subsequently, the targeting moieties are activated in response to the bacteria, and the release of entrapped antibiotics is triggered by bacteria and bacteria-secreted enzymes. The self-immolative drug delivery nanoplatform eliminates intracellular pathogenic bacteria residing in macrophages more efficiently compared to drugs alone. The in vivo dynamically monitored nanosystem also efficiently inhibited the growth of intracellular Staphylococcus aureus in infected muscles of mice with negligible systemic toxicity. The novel dual-targeting design of an all-in-one therapeutic platform can be used as an alternative strategy to reanimate antibiotic therapy against multifarious intracellular bacterial infections.

Photoactive Silver Nanoagents for Backgroundless Monitoring and Precision Killing of Multidrug-Resistant Bacteria.

Purpose: The growing prevalence of multidrug-resistant (MDR) bacteria makes it clinically urgent to develop an agent able to detect and treat infections simultaneously. Silver has served as a broad-spectrum antimicrobial since ancient times but suffers from major challenges such as moderate antimicrobial activity, nonspecific toxicity, and difficulty to be visualized in situ. Here, we propose a new photoactive silver nanoagent that relies on a photosensitizer-triggered cascade reaction to liberate Ag+ on bacterial surfaces exclusively, allowing the precise killing of MDR bacteria. Additionally, the AgNP core acts as a backgroundless surface-enhanced Raman scattering (SERS) substrate for imaging the distribution of the nanoagents on bacterial surfaces and monitoring their metabolic dynamics in the infection sites. Methods: In this strategy, the photoactive antibacterial AgNP was decorated with photosensitizers (Chlorin e6, Ce6) and Raman reporter (4-Mercaptobenzonitrile, 4-MB) to provide new opportunities for clinically monitoring and fighting MDR bacterial infections. Upon 655 nm laser activation, the Ce6 molecules produce ROS efficiently, triggering the rapid release of Ag+ from the AgNP core to kill bacteria. Poly[4-O-(α-D-glucopyranosyl)-D-glucopyranose] (GP) was introduced as bacteria-specific targeting ligands. SERS spectra of the prepared GP-Ce6/MB-AgNPs were recorded after injecting for 0.5, 4, 8, 12, 24, and 48 h to track the dynamic metabolism of the nanoagents and thus guiding the antibacterial therapy. Results: This new antimicrobial strategy exerts a dramatically enhanced antibacterial activity. The in vitro antibacterial efficiencies of this non-antibiotic technique were up to 99.6% against Methicillin-resistant Staphylococcus aureus (MRSA) and 98.8% against Escherichia coli (EC), while the in vivo antibacterial efficiencies for MRSA- and Carbapenem-resistant Pseudomonas aeruginosa (CRPA)-infected mice models were 96.8% and 93.6%, respectively. Besides, backgroundless SERS signal intensity of the wound declined to the level of normal tissue until 24 h, indicating that the nanoagents had been completely metabolized from the infected area. Conclusion: Given the backgroundless monitoring ability, high antibacterial efficacy, and low toxicity, the photoactive cascading agents would hold great potential for MDR-bacterial detection and elimination in diverse clinical settings.

Glycosylated Nanotherapeutics with ß-Lactamase Reversible Competitive Inhibitory Activity Reinvigorates Antibiotics against Gram-Negative Bacteria.

Antibiotics are currently first-line therapy for bacterial infections. However, the curative effect of antibiotic remedies is limited due to increasingly prevalent bacterial resistance. The strategy to reverse intrinsic acquired drug resistance presents a promising option for reinvigorating antibiotic therapy. Here, we developed a ß-lactamase-inhibiting macromolecule composed of benzoxaborole and dextran for precise transport of ß-lactam antibiotics to strains overexpressing ß-lactamase. Benzoxaborole-derived nanotherapeutics enabled specific recognition and rapid internalization, and the nanotherapeutics with a high affinity toward bacteria distinctly inhibited the catalytic activity of bacterially secreted ß-lactamase by a reversible competitive mechanism. Thus, the system entrapping cefoxitin harbored a significantly enhanced ability to kill drug-resistant Escherichia coli compared to the ability of the drug by specifically overcoming the membrane barrier and acquired resistance mechanism of ß-lactamase overproduction. The reversible competitive nanotherapeutics exhibited a robust therapeutic efficacy in rat wounds infected with drug-resistant bacteria; the efficacy was due to efficient bacterial elimination and collateral benzoxaborole-dependent amelioration of the inflammatory response. The above results offered insights into the facile design of precise macromolecular adjuvants to exclusively reverse the acquired bacterial resistance mechanism and increase the utility of antibiotic therapies against antibiotic-resistant bacterial infections.

Bioadhesive glycosylated nanoformulations for extended trans-corneal drug delivery to suppress corneal neovascularization.

Eye-drop formulations as conventional regimens to tackle ocular diseases are far from efficient due to the rapid clearance by eye tears and the blockage of the corneal epithelium barrier. Here, we describe a bioadhesive glycosylated nanoplatform with boric acid pendants as a drug carrier for noninvasive trans-corneal delivery of drugs to treat corneal neovascularization (CNV), a serious corneal disease resulting in significant vision impairment. This biocompatible nanoplatform is formulated from a synthetic amphiphilic boric acid-based copolymer self-assembling to form highly stable micelles with a high loading capacity for dexamethasone (DEX). The nanoplatform is demonstrated to be in contact with the corneal epithelium for a long period under the bioadhesive function of boric acid modules and releases the drug over 96 h in a controlled manner. Our results also suggest that the nanoplatform can be efficiently internalized by corneal epithelial cells in vitro and realize transcytosis in vivo to greatly enhance the transcorneal penetration of the loaded drugs into the pathological corneal stroma. On topical application against rat corneal alkali burn, the nanoformulation presents more robust efficacy on neovascularization suppression and inflammation elimination than free DEX with a negligible effect on normal tissues. This bioadhesive strategy which focuses on extending ocular drug retention and improving trans-corneal drug delivery not only highlights an approach for alternative noninvasive therapy of CNV but also provides a versatile paradigm for other biomedical applications by overcoming protective barriers.

Epithelium-Penetrable Nanoplatform with Enhanced Antibiotic Internalization for Management of Bacterial Keratitis.

A standardized regimen for addressing the adverse effects of bacterial keratitis on vision remains an intractable challenge due to poor epithelial penetration and a short corneal retention time. In this study, a new strategy is proposed to implement the direct transport of antibiotics to bacteria-infected corneas via topical administration of an epithelium-penetrable biodriven nanoplatform, thereby enabling the efficacious treatment of bacterial keratitis. The nanoplatforms were composed of amphiphilic glycopolymers containing boron dipyrromethene and boronic acid moieties with stable fluorescence characteristics and the ability to potentiate epithelial penetration deep into the cornea. The boronic acid-derived nanoplatforms enabled efficient cellular internalization through the high affinity of boric acid groups for the diol-containing bacterial cell wall, resulting in enhanced drug penetration and retention inside the pathogenic bacteria. The bacterial cells formed agglomerations after incorporating the nanoplatforms along with a special mechanism to release the encapsulated cargo in response to in situ bacteria. Compared with the drug alone, this smart system achieved enhanced bacterial mortality and attenuated inflammation associated with Staphylococcus aureus-induced keratitis in rats, demonstrating a paradigm for targeted ocular drug delivery and an alternative strategy for managing bacterial keratitis or other bacterial infections by heightening corneal permeability and transcorneal bioavailability.

Ag-Conjugated graphene quantum dots with blue light-enhanced singlet oxygen generation for ternary-mode highly-efficient antimicrobial therapy.

The increasing prevalence of antibiotic resistance highlights the need for new antibacterial drugs and, in particular, the development of alternative approaches such as photodynamic therapy (PDT) and photothermal therapy (PTT) to manage this growing issue. In the present study, a broad-spectrum antibacterial system was produced in which Ag nanoparticle-conjugated graphene quantum dots (GQD-AgNP) were utilised as a blue light-enhanced nanotherapeutic for efficient ternary-mode antimicrobial therapy. The successful conjugation of AgNPs onto the surface of GQDs can significantly improve the production of reactive oxygen species in light-activatable GQDs and the transformation of light energy to hyperthermia with high efficiency. There was a remarkable increase in the sample temperature of nearly 40 °C via photoexcitation after only 10 min of 450 nm laser exposure (14.2 mW cm-2). The hybrids exhibited much more efficient bactericidal capability against both Gram-negative and Gram-positive bacteria compared with GQDs alone, using 450 nm light irradiation. This is likely a consequence of their enhanced PDT, concomitant PTT, and the synergistic function of AgNPs. The antibacterial mechanism of the new-style nanocomposites was found to irreversibly destroy the bacterial membrane structure, leading to the leaking out of the cytoplasmic contents and the death of the bacteria. At low doses, the biocompatible GQD-AgNP hybrids promoted healing in bacteria-infected rat wounds, with negligible adverse impact to the normal tissue, indicating a promising future for combined photodynamic and photothermal antibacterial applications in clinical medicine.

A Bioadhesive Nanoplatform Enhances the Permeation of Drugs Used to Treat Diabetic Macular Edema.

The management of diabetic macular edema (DME), a condition that leads to an irreversible and severe visual impairment, remains a substantial challenge worldwide. In this study, we developed a bioadhesive nanoplatform with enhanced drug penetration to explore alternative treatment modalities for DME. This nanoparticulate formulation consisted of a sequence of an amphiphilic phenylboronic acid-based block and random glycopolymer with a high loading capacity for dexamethasone (DEX) of up to 20% and sustained drug release in vitro at a clinically relevant dose. The bioadhesive nanocarriers penetrated the sclera and choroid and were distributed in the retina under the action of phenylboronic acid to further promote drug permeation and retention in target lesions. The pathological analysis, electroretinography examination and immunofluorescence staining revealed that the nanoformulation of DEX much more markedly reduced the symptoms of and inflammation associated with DME than the drug alone, without affecting the function of the retina. Bioadhesive drug delivery systems are expected to be a feasible approach to treat DME and other fundus diseases.

Bioinspired Heteromultivalent Ligand-Decorated Nanotherapeutic for Enhanced Photothermal and Photodynamic Therapy of Antibiotic-Resistant Bacterial Pneumonia.

Pseudomonas aeruginosa can cause a multitude of inflammations in humans. Due to its ability to form biofilm, the bacteria show durable resistance to drugs. Herein, we developed a heteromultivalent ligand-decorated nanotherapeutic inspired by living system for inhibition of antibiotic-resistant bacterial pneumonia. The nanotherapeutic with a heteromultivalent glycomimetic shell can specifically recognize P. aeruginosa to inhibit its biofilm formation and protect native cells from bacterial infection; the rate of biofilm inhibition was up to 85%. The nanotherapeutic with a bioresponsive hydrophobic core can protonate and control drug release in the microenvironment of bacterial infections. By utilizing these properties, the nanotherapeutics can effectively penetrate the internal structure of biofilms to release the drug, dispersing the biofilm by over 80% under laser irradiation. In vivo bioinspired nanotherapeutics have the potential to efficiently inhibit antibiotic-resistant P. aeruginosa-induced pneumonia. Collectively, we expect biomimicking systems to be the next generation of prevention and treatment as integrated antibacterial agents against P. aeruginosa.

In situ real-time tracing of hierarchical targeting nanostructures in drug resistant tumors using diffuse fluorescence tomography.

Nanoparticles that respond to specific endogenous or exogenous stimuli in tumor tissues are actively being developed to address multidrug resistance owing to multiple advantages, including a prolonged circulation time, enhanced permeability and retention effect, and superior cellular uptake. Although some exciting results have been obtained, existing nanoparticles have limited routes to overcome the drug resistance of tumor cells; this limitation results in a failure to ablate resistant tumors via intravenous administration. To resolve this dilemma, we developed a smart theranostic nanoplatform with programmable particle size, activatable target ligands and in vivo multimodal imaging. This nanoplatform, which includes stealth zwitterionic coating, was shown to be quickly trapped in tumor tissue from the blood circulation within 5 min. Subsequently, the targeting moieties were activated in response to the acidic tumor microenvironment by triggering the zwitterionic shell detachment, driving the peeled nanoparticles to penetrate into tumor cells. These smart nanoparticles completely inhibited drug-resistant tumor growth and did not cause any damage to normal organ tissues in live animals. The designed nanoplatforms simultaneously acted as a nanoprobe for fluorescence imaging. Moreover, we also used noninvasive pharmacokinetic diffuse fluorescence tomography (DFT) to dynamically monitor and in situ real-time trace the nanoplatforms' behavior throughout the entire tumor in live animals. The nanoplatforms enabled rapid drug accumulation and deep penetration throughout the entire tumor. The rate of drug accumulation after the administration of nanoplatforms was five-fold higher compared with that after the administration of the free drug, which resulted in increased drug delivery efficiency and improved antitumor efficacy. Collectively, this hierarchical vehicle design provides promising insights for the development of theragnosis for multidrug resistant tumors.

A Biomimetic Non-Antibiotic Approach to Eradicate Drug-Resistant Infections.

The chronic infections by pathogenic Pseudomonas aeruginosa (P. aeruginosa) remain to be properly addressed. In particular, for drug-resistant strains, limited medication is available. An in vivo pneumonia model induced by a clinically isolated aminoglycoside resistant strain of P. aeruginosa is developed. Tobramycin clinically treating P. aeruginosa infections is found to be ineffective to inhibit or eliminate this drug-resistant strain. Here, a newly developed non-antibiotics based nanoformulation plus near-infrared (NIR) photothermal treatment shows a remarkable antibacterial efficacy in treating this drug-resistant pneumonia. The novel formulation contains 50-100 nm long nanorods decorated with two types of glycomimetic polymers to specifically block bacterial LecA and LecB lectins, respectively, which are essential for bacterial biofilm development. Such a 3D display of heteromultivalent glycomimetics on a large scale is inspired by the natural strengthening mechanism for the carbohydrate-lectin interaction that occurs when bacteria initially infects the host. This novel formulation shows the most efficient bacteria inhabitation and killing against P. aeruginosa infection, through lectin blocking and the near-infrared-light-induced photothermal effect of gold nanorods, respectively. Collectively, the novel biomimetic design combined with the photothermal killing capability is expected to be an alternative treatment strategy against the ever-threatening drug-resistant infectious diseases when known antibiotics have failed.