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.

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.

Oxygen Self-Supplying Nanotherapeutic for Mitigation of Tissue Hypoxia and Enhanced Photodynamic Therapy of Bacterial Keratitis.

Hypoxia, a common characteristic of bacterial infections, is known to be closely associated with the emergence of multidrug-resistant bacteria, which hastens the need to develop advanced microbicides and antibacterial techniques. Photodynamic therapy is a promising strategy to reduce bacterial antibiotic resistance and employs photosensitizers, excitation light sources, and sufficient oxygen to generate toxic reactive oxygen species (ROS). The inherent limitation of PDT is that the generation of ROS is restricted by the hypoxic microenvironment in infection sites. Here, an oxygen self-supplying nanotherapeutic is developed to enhance antibacterial activity against multidrug-resistant bacteria on the basis of fluorinated boron dipyrromethene (BODIPY)-based glycomimetics. The nanotherapeutic not only could capture the bacteria efficiently but also was able to act as an oxygen carrier to relieve the hypoxic microenvironment of bacterial infections, thus achieving enhanced PDT efficacy. In a Pseudomonas aeruginosa infection of a rat cornea, typical administration of the nanotherapeutic decreased the infiltrate and showed a faster healing capacity in comparison with BODIPY-based glycomimetics. Self-supplying oxygen nanotherapeutics that relieve the hypoxic microenvironment and interfere with bacterial colonization have been shown to be a promising candidate for the management of drug-resistant microbial keratitis.

An on-demand nanoplatform for enhanced elimination of drug-resistant bacteria.

The Gram-negative opportunistic pathogen Pseudomonas aeruginosa is endowed with intrinsic resistance to antibiotics. It is essential to explore alternative techniques to supplement the arsenal of methods to kill drug-resistant bacteria. Herein, we established an "on-demand" nanoplatform based on acid-degradable scaffolds by conjugating glycomimetic-based galactose ligands to target a key lectin on P. aeruginosa and guanidine moieties. This nanoplatform could capture bacteria through ligand-receptor interactions and electrostatic interactions, and subsequently reactive oxygen species produced by entrapped photodynamic agent Ce6 under light irradiation eliminated drug-resistant P. aeruginosa and its biofilm. Approximately 95% of the planktonic bacteria were killed and more than 70% of the biofilm was disrupted under light irradiation. This strategy of copolymer modification could improve the biocompatibility and therapeutic efficiency levels of antibacterial therapeutics through the targeting of function. Hence, utilizing this smart nanoplatform may be of significance in developing new strategies to solve the growing problem of bacterial resistance.

Protonation-Activity Relationship of Bioinspired Ionizable Glycomimetics for the Growth Inhibition of Bacteria.

Variations in physiological parameters (i.e., pH, redox potential, and ions) for distinct types of diseases make them attractive targets. Ionizable groups capable of pH-dependent charge conversion impart pH-switchable materials under acid condition through the protonation effect, which stimulates the emergence of various pH-inspired materials. However, it is confusing to distinguish preferable groups for high-efficiency drug-delivery vehicles attributing to the lack of perceiving the relationship between protonation and activity. Herein, we developed a series of bioinspired ionizable glycomimetics responses to the ambient variation from physiological environment (pH 7.4) to bacterial infectious acidic microenvironment (pH 6.0) to explore the protonation-activity relationship of various ionizable groups. The nanoparticles are coated with bacterial adhesion molecules galactose and fucose to target Pseudomonas aeruginosa. Moreover, the particle cores were composed of ionizable polymers responding to acidic microenvironment changes and entrapped antibiotic payload. Ionizable glyconanoparticles targeted bacteria and local cues as triggers to transfer payloads in on-demand patterns for the inhibition of bacteria-related infection. Significantly, we find that the nanoparticles with the pH-sensitive block of ionizable poly(2-(diisopropylamino)ethyl methacrylate) (pDPA) exhibit predominant bacterial adhesion and killing and growth inhibition of biofilm in acid environment (pH 6.0) due to the ionizable polymer protonation effect with more positive charge cooperated with the lectin-targeted effect of polysaccharide causing a huge bacterial aggregation and a highly favorable germicidal effect. The nanoparticles with poly(2-(hexamethyleneimino)ethyl methacrylate) (pHMEMA) have suboptimal antibacterial activity but advanced protonation at pH 6.3 compared to pDPA at 6.1, suggesting its selection as an applicable pH-switchable group for a slightly higher acid microenvironment like tumor (pH 6.9-6.5) because of the efficient performance after protonation than at deprotonation. On the other hand, the glycomimetic containing poly(2-(dibutylamino)ethyl methacrylate) (pDBA) as a pH-sensitive moiety displayed weak antimicrobial activity and superior stability before protonation (pH 4.7), which make it possible to prevent premature drug leakage, suggesting that pDBA is a good candidate to be applied to construct pH-sensitive drug-delivery carriers for the treatment of bacteria-related infection with a low acidic microenvironment. Overall, the structure-activity relationship of ionizable glycomimetics for the inhibition of bacteria signifies not only the development of a drug-delivery system but also the mechanism-dependent treatment of nanomedicine for infectious diseases.