Currently, microbial infections have posed an arduous challenge to global public health, whereas the rise of antibiotic resistance is rendering traditional antibiotic therapies futile, prompting the development of new antimicrobial technologies. Photoactive nanomaterials have thus garnered a thriving interest for disinfection owing to their superior antibacterial efficaciousness, favorable biosafety, and rapidness and spatiotemporal precision in excreting bactericidal actions. The review summarizes recent advances and emerging trends in the design, nanoengineering, and bioapplications of photoactive antimicrobials. It commences by elaborating fundamental theories on bacterial resistance, and antibacterial mechanisms of nanomaterials and phototherapy. Subsequently, the regulation of the antibacterial effectiveness of photoactive nanomaterials is comprehensively discussed, centering on criteria and strategies for tuning photoabsorption spectra, photothermal conversion, and photocatalytic efficiency, alongside tactics for enabling synergistic therapies. This is followed by comparative analyses of techniques and modalities for synthesizing and engineering photoactive nanomaterials with diverse structures, forms, and functionalities. Thereafter, the state‐of‐the‐art applications of phototherapies across various medical sectors are portrayed, and key challenges and opportunities are finally discussed to spur future innovations and translation. This review is envisaged to provide useful guidance for devising and developing nanomaterials‐based photoresponsive antimicrobials with application‐specific materials properties and biological functions.

Design and Nanoengineering of Photoactive Antimicrobials for Bioapplications: from Fundamentals to Advanced Strategies

Photodynamic therapy (PDT) is a long known, FDA approved, and highly promising therapeutic modality, which is still developing. Photosensitizers (PSs) are at the core of PDT action and a worldwide effort has been put to develop PSs having multiple functionalities. In the design of new generation PSs, an attractive approach is to target organelles to get an exceptional therapeutic outcome as damaging these vital subcellular compartments improve the photocytotoxic effect of the PSs. To this end, small molecule organic PSs are suitable candidates due to ease of chemical modification, which allows simple implementation of the organelle targeting units on the PS structure. Furthermore, they hold unique characteristics such as low dark toxicity, high reactive oxygen species (ROS) generation capacity, biocompatibility, and tunable photophysical and photochemical properties. Accordingly, a wide variety of organelle-targeted organic PSs have been developed and proved to be highly successful both in therapeutic action and bioimaging applications. In this review article, we have summarized the recent advances in organelle localizing organic-based PSs by discussing the design principles, organelle targeting strategies and related bio-applications in detail. PSs targeting seven different organelles have been included. We have also highlighted the current challenges and gave a comprehensive outlook for the future of organelle-targeted PSs. 

Recent advances in organelle-targeted organic photosensitizers for efficient photodynamic therapy

Atherosclerosis (AS) is the formation of plaques in blood vessels, which leads to serious cardiovascular diseases. Current research has disclosed that the formation of AS plaques is highly related to the foaming of macrophages. However, there is a lack of detailed molecular biological mechanisms. We proposed a "live sensor" by grafting a tetrazine-based ratiometric NO probe within macrophages through metabolic and bio-orthogonal labeling. This "live sensor" was proved to target the AS plaques with a diameter of only tens of micrometers specifically and visualized endogenous NO at two lesion stages in the AS mouse model. The ratiometric signals from the probe confirmed the participation of NO during AS and indicated that the generation of endogenous NO increased significantly as the lesion progressed. Our proposal of this "live sensor" provided a native and smart strategy to target and deliver small molecular probes to the AS plaques at the in vivo level, which can be used as universal platforms for the detection of reactive molecules or microenvironmental factors in AS.

Tetrazine-Based Ratiometric Nitric Oxide Sensor Identifies Endogenous Nitric Oxide in Atherosclerosis Plaques by Riding Macrophages as a Smart Vehicle.

Sepsis, which is the most severe clinical manifestation of acute infection and has a mortality rate higher than that of cancer, represents a significant global public health burden. Persistent methicillin-resistant Staphylococcus aureus (MRSA) infection and further host immune paralysis are the leading causes of sepsis-associated death, but limited clinical interventions that target sepsis have failed to effectively restore immune homeostasis to enable complete eradication of MRSA. To restimulate anti-MRSA innate immunity, we developed CRV peptide-modified lipid nanoparticles (CRV/LNP-RNAs) for transient in situ programming of macrophages (MΦs). The CRV/LNP-RNAs enabled the delivery of MRSA-targeted chimeric antigen receptor (CAR) mRNA (SasA-CAR mRNA) and CASP11 (a key MRSA intracellular evasion target) siRNA to MΦs in situ, yielding CAR-MΦs with boosted bactericidal potency. Specifically, our results demonstrated that the engineered MΦs could efficiently phagocytose and digest MRSA intracellularly, preventing immune evasion by the "superbug" MRSA. Our findings highlight the potential of nanoparticle-enabled in vivo generation of CAR-MΦs as a therapeutic platform for multidrug-resistant (MDR) bacterial infections and should be confirmed in clinical trials.

mRNA-Laden Lipid-Nanoparticle-Enabled in Situ CAR-Macrophage Engineering for the Eradication of Multidrug-Resistant Bacteria in a Sepsis Mouse Model.

This article provides a comprehensive overview of recent advances in the development of bioorthogonally activated probes for labelling and precise in situ fluorescence imaging both in vitro and in vivo . 

Bioorthogonally activated probes for precise fluorescence imaging

Multidrug-resistant (MDR) bacteria cause severe clinical infections and a high mortality rate of over 40% in patients with immunodeficiencies. Therefore, more effective, broad-spectrum, and accurate treatment for severe cases of infection is urgently needed. Here, we present an adoptive transfer of macrophages loaded with a near-infrared photosensitizer (Lyso700D) in lysosomes to boost innate immunity and capture and eliminate bacteria through a photodynamic effect. In this design, the macrophages can track and capture bacteria into the lysosomes through innate immunity, thereby delivering the photosensitizer to the bacteria within a single lysosome, maximizing the photodynamic effect and minimizing the side effects. Our results demonstrate that this therapeutic strategy eliminated MDR Staphylococcus aureus (MRSA) and Acinetobacter baumannii (AB) efficiently and cured infected mice in both two models with 100% survival compared to 10% in the control groups. Promisingly, in a rat model of central nervous system bacterial infection, we performed the therapy using bone marrow-divided macrophages and implanted glass fiber to conduct light irradiation through the lumbar cistern. 100% of infected rats survived while none of the control group survived. Our work proposes an efaficient and safe strategy to cure MDR bacterial infections, which may benefit the future clinical treatment of infection. 

Adoptive macrophage directed photodynamic therapy of multidrug-resistant bacterial infection

The techniques to quantitatively monitor environmental factors surrounding the bacterial outer surface rather than the host's subcellular regions (e.g., lysosomes) should be the key to evaluate bacterial immune escape behavior. We report wild Staphylococcus aureus (SA) and methicillin-resistant Staphylococcus aureus (MRSA) labeled with a fluorescent resonance energy transfer probe, 4SR-L-BDP, on their outer surfaces as smart live sensors to quantify interfacial pH. The dual emission of 4SR-L-BDP affords high sensitivity to pH change in a ratiometric way in the pH range of 4-8 with high precision. Notably, 4SR-L-BDP possesses an anchoring group to fix on the bacterial surface for sensing the microenvironment encountered. Super-resolution imaging clearly demonstrates the specific labeling of bacterial membranes. These live sensors are applied in two-channel ratiometric imaging to dynamically visualize and quantify their interfacial pH changes during infection of macrophages. It is found that the interfacial pH of MRSA is lower by 0.2 units compared to that of SA. Such small but critical difference in pH reflects MRSA's ability to adapt to microenvironmental pH inside macrophages. These labeled bacteria as live sensors are also proven to be practically applicable in mice models with immune deficiency and immune activation.

Outer Surface-Labeled Bacteria as Live Sensors Accurately Quantitating Interfacial pH: A Smart Technique for Antimicrobial Resistance.

A Mitochondria-Targeted Dye for Investigating Mo Mineral Powder Induced Cytotoxicity through SIM Super-Resolution Imaging.

There has been a vision to conduct therapy using sunlight since ancient Greece, Egypt, and India. In modern medicine, photodynamic therapy is one popular form of therapy that uses light to excite photosensitizers to eliminate malignant and other diseased cells. It offers highly effective and broad-spectrum therapeutic efficacy. Yet, there are several hindrances to a real treatment of disease through photodynamic therapy, such as the limitation on the irradiation depth and areas, the regulation of side effects, etc. Usually, the patients should be kept in a dark environment during and after the therapeutic process for days to avoid side effects induced by light in daily life, not mention to conduct the phototherapy through sunbathing. Based on the above consideration, we propose an innovative idea to bring photodynamic therapy back to the origin of phototherapy-bathing in the sunshine. Namely, we designed a “live drug”, as a smart hunter, named A-RAWs, by loading an “off-on” type of photosensitizer in macrophages to solve two technical problems. Firstly, to find and capture bacteria accurately, and then transport these bacteria to the epidermis through the blood capillary, where sunlight is reachable. Secondly, to minimize the potential side effects and maximize the therapeutic time windows and efficacy by using bacteria as the trigger of the photodynamic effect. Specifically, we first designed and synthesized a lysosome-targeted and inflammation-activated NIR photosensitizer (Lyso710A), and loaded it in the lysosomes of macrophages. These “armed” macrophages were transferred into the infected host to capture deep-tissue bacteria through innate immunity and transport the captured bacteria through the bloodstream to superficial skin. Finally, the pathogenic bacteria are killed by the photodynamic effect when transported to the epidermis and receive sunbathing. In vivo experiment demonstrates a 100% therapeutic efficiency on systemic bacterial infection model. We also demonstrated the working mechanism of this “live drug” using a lung infection model. This hunter demonstrates high intelligence to break the limitations of current photodynamic therapy and executes photodynamic therapy of deep-tissue bacterial infection simply by bathing in the sunshine.

Armed Macrophages as Hunters for Photodynamic Therapy of Systemic Bacterial Infections by Bathing in the Sunshine

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