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Developing a universal nanoplatform for efficient delivery of various drugs to target sites is urgent for overcoming various biological barriers and realizing combinational cancer treatment. Nanogels, with the advantages of both hydrogels and nanoparticles, may hold potential for addressing the above issue. Here, a dual-responsive nanogel platform (HPC nanogel) is constructed using β-cyclodextrin-conjugated hyaluronic acid (HA-βCD), polyethyleneimine (PEI), and cisplatin. HA-βCD and PEI compose the skeleton of the nanogel, and cisplatin molecules provide the junctions inside the skeleton, thus affording a multiple interactions-based nanogel. Besides, HA endows the nanogel with hyaluronidase (HAase)-responsiveness, and cisplatin guarantees the glutathione (GSH)-responsive ability, which make the nanogel a dual-responsive platform that can degrade and release the loaded drugs when encountering HAase or GSH. Additionally, the HPC nanogel possesses excellent small-molecule drug and protein loading and intracellular delivery capabilities. Especially, for proteins, their intracellular delivery via nanogels is not hindered by serum proteins, and the enzymes delivered into cells still maintain their catalytic activities. Furthermore, the nanogel can codeliver different cargoes to achieve "cocktail" chemotherapeutic efficacy and realize combination cancer therapy. Overall, the HPC nanogel can serve as a multifunctional platform capable of delivering desired drugs to treat cancer or other diseases.

Ionic liquids (ILs), although being a class of promising green solvents, have received many reports on the toxicity to living organisms. In this work, aiming at elucidating the disruptive effect of ILs to cell membrane lipid rafts, we investigated the effect of three 1-octylimidazolium-based ILs on the properties of the liquid ordered phase (L

Cancer cells frequently exhibit resistance to various molecular and nanoscale drugs, which inevitably affects the drugs' therapeutic outcomes. Overexpression of glutathione (GSH) has been observed in many cancer cells, and solid evidence has corroborated the resulting tumor resistance to a variety of anticancer therapies, suggesting that this biochemical characteristic of cancer cells can be developed as a potential target for cancer treatments. The single treatment of GSH-depleting agents can potentiate the responses of the cancer cells to different cell death stimuli; therefore, as an adjunctive strategy, GSH depletion is usually combined with mainstream cancer therapies for enhancing the therapeutic outcomes. Propelled by the rapid development of nanotechnology, GSH-depleting agents can be readily constructed into anticancer nanomedicines, which have shown a steep rise over the past decade. Here, we review the common GSH-depleting nanomedicines which have been widely applied in synergistic cancer treatments in recent years. Some current challenges and future perspectives for GSH depletion-based cancer therapies are also presented. With the understanding of the structure-property relationship and action mechanisms of these biomaterials, we hope that the GSH-depleting nanotechnology will be further developed to realize more effective disease treatments and even achieve successful clinical translations.

Plasma membrane (PM), a fundamental building component of a cell, is responsible for a variety of cell functions and biological processes. However, it is still challenging to acquire its morphology and morphological variation information via an effective approach. Herein, we report a PM imaging study regarding an aggregation-induced emission luminogen (AIEgen) called tetraphenylethylene-naphthalimide+ (TPE-NIM+), which is derived from our previously reported tetraphenylethylene-naphthalimide (TPE-NIM). The designed AIEgen (TPE-NIM+) shows significant characteristics of ultrafast staining, high photostability, wash-free property, and long retention time at the PM, which can structurally be correlated with its positively charged quaternary amine and hydrophobic moiety. TPE-NIM+ is further applied for staining of different cell lines, proving its universal PM imaging capability. Most importantly, we demonstrate that TPE-NIM+ can clearly delineate the contours of densely packed living cells with high cytocompatibility. Therefore, TPE-NIM+ as a PM imaging reagent superior to currently available commercial PM dyes shall find a number of applications in the biological/biomedical fields and even beyond.

Preservation of the intact cell morphology of bacteria is recognized as one important cause of bacterial drug resistance, and hence developing new antibacterial agents capable of fighting against bacteria

Bacterial infection has become an urgent health problem in the world. Especially, the evolving resistance of bacteria to antibiotics makes the issue more challenging, and thus new treatments to fight these infections are needed. Antibacterial photodynamic therapy (aPDT) is recognized as a novel and promising method to inactivate a wide range of bacteria with few possibilities to develop drug resistance. However, the photosensitizers (PSs) are not effective against Gram-negative bacteria in many cases. Herein, we use conjugated meso-tetra(4-carboxyphenyl)porphine (TCPP) and triaminoguanidinium chloride (TG) to construct self-assembled cationic TCPP-TG nanoparticles (NPs) for efficient bacterial inactivation under visible light illumination. The TCPP-TG NPs can rapidly adhere to both Gram-negative and Gram-positive bacteria and display promoted singlet oxygen (1O2) generation compared with TCPP under light irradiation. The high local positive charge density of TCPP-TG NPs facilitates the interaction between the NPs and bacteria. Consequently, the TCPP-TG NPs produce an elevated concentration of local 1O2 under light irradiation, resulting in an extraordinarily high antibacterial efficiency (99.9999% inactivation of the representative bacteria within 4 min). Furthermore, the TCPP-TG NPs show excellent water dispersity and stability during 4 months of storage. Therefore, the rationally designed TCPP-TG NPs are a promising antibacterial agent for effective aPDT.

Antimicrobial photodynamic therapy (APDT) is a promising alternative to traditional antibiotics for the treatment of bacterial infections, which inactivates a broad spectrum of bacteria. However, many traditional photosensitizers (PSs) are hydrophobic with poor water solubility and easy aggregation. On the other hand, some light sources such as ultraviolet (UV) have poor penetration and high cytotoxicity. Both issues lead to undesired photodynamic therapy efficacy. To overcome these issues, we develop a novel water-soluble natural PS (sorbicillinoids) obtained by microbial fermentation using recombinant filamentous fungus Trichoderma reesei. Sorbicillinoids could effectively generate singlet oxygen (1O2) under UV light irradiation and ultimately display photoinactivation activity on Gram-positive bacteria including Staphylococcus aureus, Bacillus subtilis, and Micrococcus luteus but not Gram-negative ones such as Escherichia coli and Proteus vulgaris. Sorbicillinoids were found to enter S. aureus but not E. coli. S. aureus treated with sorbicillinoids and UV light displayed high levels of intracellular reactive oxygen species (ROS), notable DNA photocleavage, and compromised cell semipermeability without overt cell membrane disruption, none of which was found in the treated E. coli. All these contribute to the sorbicillinoid-based photoinactivation of Gram-positive bacteria. Moreover, the dark toxicity and phototoxicity on mammalian cells or hemolysis activity of sorbicillinoids is negligible, showing its excellent biocompatibility. This study expands the utilization of UV light for surface sterilization to disinfection in solution. Therefore, sorbicillinoids, a type of secondary metabolite from fungus, have a promising future as a new PS for APDT using a nontoxic dose of UV irradiation.

Many noble metal-based nanoparticles have emerged for applications in cancer radiotherapy in recent years, but few investigations have been carried out for palladium nanoparticles. Herein, palladium nanosheets (Pd NSs), which possess a sheetlike morphology with a diameter of ∼14 nm and a thickness of ∼2 nm, were utilized as a sensitizer to improve the performance of radiotherapy. It was found that Pd NSs alone did not decrease the cell viability after treatment for as long as 130 h, suggesting the excellent cytocompatibility of the nanoagents. However, the viability of cancer cells treated with X-ray irradiation became lower, and the viability became even lower if the cells were co-treated with X-ray and Pd NSs, indicating the radiosensitization effect of Pd NSs. Additionally, compared with X-ray irradiation, the combined treatment of Pd NSs and X-ray irradiation induced the generation of more DNA double-stranded breaks and reactive oxygen species within cancer cells, which eventually caused elevated cell apoptosis. Moreover, in vivo experiments also verified the radiosensitization effect and the favorable biocompatibility of Pd NSs, indicating their potential for acquiring satisfactory in vivo radiotherapeutic effect at lower X-ray doses. It is believed that the present research will open new avenues for the application of noble metal-based nanoparticles in radiosensitization.

Clinically approved doxorubicin (Dox)-loaded liposomes (e.g., Doxil) guarantee good biosafety, but their insufficient nuclear delivery of Dox (

Developing intrinsically mitochondria-targetable nanosystems for subcellular structure-oriented precise cancer therapy is highly desirable. Here, we conjugate the cluster determinant 44 (CD44)-targetable hyaluronic acid (HA) with cholesterol-poly(ethylene glycol)2k-NH2 and mitochondria-acting IR825-NH2 (a cyanine dye) to construct a self-assembled nanostructure (abbreviated as HA-IR825-Chol) for photothermal therapy. The HA-IR825-Chol exhibits improved photostability and desirable photothermal properties, and can rapidly and substantially enter CD44-overexpressed cancer cells and selectively accumulate in the mitochondria of the cells. Upon near-infrared laser irradiation, it can induce severe mitochondrial damage, which causes cytochrome c release and triggers cell apoptosis. Furthermore, we demonstrate the feasibility of loading the chemotherapeutics 10-hydroxycamptothecin (HCPT) into the hydrophobic cores of HA-IR825-Chol NPs for combined chemo-photothermal therapy. HCPT encapsulated within HA-IR825-Chol achieves significantly increased cellular uptake and simultaneous mitochondrial and nuclear localization, leading to the release of cytochrome c from mitochondria and upregulation of cleaved caspase-3, both of which contribute to the cell apoptosis/death. In vivo experiments reveal the excellent tumor-targeting ability of HA-IR825-Chol/HCPT, ensuring the efficient tumor eradication by the chemo-photothermal therapy. This work exemplifies the development of an intrinsically mitochondria-targetable nanocarrier for precise subcellular structure-localized drug delivery, and the Chol-mediated rapid and massive endocytosis of the nanoagents may represent a robust strategy for enhancing the efficacies of nanomedicines.

This study aimed to add two functional components—antibacterial 45S5BGs particles and AIE nanoparticles (TPE-NIM+) with bioprobe characteristics—to the guided tissue regeneration (GTR) membrane, to optimize the performance. The PLGA/BG/TPE-NIM+ membrane was synthesized. The static water contact angle, morphologies, and surface element analysis of the membrane were then characterized. In vitro biocompatibility was tested with MC3T3-E1 cells using CCK-8 assay, and antibacterial property was evaluated with Streptococcus mutans and Porphyromonas gingivalis by the LIVE/DEAD bacterial staining and dilution plating procedure. The fluorescence staining of bacteria was observed by Laser Scanning Confocal Microscope. The results showed that the average water contact angle was 46°. In the cytotoxicity test, except for the positive control group, there was no significant difference among the groups (p > 0.05). The antibacterial effect in the PLGA/BG/TPE-NIM+ group was significantly (p < 0.01), while the sterilization rate was 99.99%, better than that in the PLGA/BG group (98.62%) (p < 0.01). Confocal images showed that the membrane efficiently distinguished G+ bacteria from G− bacteria. This study demonstrated that the PLGA/BG/TPE-NIM+ membrane showed good biocompatibility, efficient sterilization performance, and surface mineralization ability and could be used to detect pathogens in a simple, fast, and wash-free protocol.

Antibody-based cancer therapy, one of the most significant therapeutic strategies, has achieved considerable success and progress over the past decades. Nevertheless, obstacles including limited tumor penetration, short circulation half-lives, undesired immunogenicity, and off-target side effects remain to be overcome for the antibody-based cancer treatment. Owing to the rapid development of nanotechnology, antibody-containing nanomedicines that have been extensively explored to overcome these obstacles have already demonstrated enhanced anticancer efficacy and clinical translation potential. This review intends to offer an overview of the advancements of antibody-incorporated nanoparticulate systems in cancer treatment, together with the nontrivial challenges faced by these next-generation nanomedicines. Diverse strategies of antibody immobilization, formats of antibodies, types of cancer-associated antigens, and anticancer mechanisms of antibody-containing nanomedicines are provided and discussed in this review, with an emphasis on the latest applications. The current limitations and future research directions on antibody-containing nanomedicines are also discussed from different perspectives to provide new insights into the construction of anticancer nanomedicines.

Chemodynamic therapy (CDT), a novel cancer therapeutic strategy defined as the treatment using Fenton or Fenton-like reaction to produce •OH in the tumor region, was first proposed by Bu, Shi, and co-workers in 2016. Recently, with the rapid development of Fenton and Fenton-like nanomaterials, CDT has attracted tremendous attention because of its unique advantages: 1) It is tumor-selective with low side effects; 2) the CDT process does not depend on external field stimulation; 3) it can modulate the hypoxic and immunosuppressive tumor microenvironment; 4) the treatment cost of CDT is low. In addition to the Fe-involved CDT strategies, the Fenton-like reaction-mediated CDT strategies have also been proposed, which are based on many other metal elements including copper, manganese, cobalt, titanium, vanadium, palladium, silver, molybdenum, ruthenium, tungsten, cerium, and zinc. Moreover, CDT has been combined with other therapies like chemotherapy, radiotherapy, phototherapy, sonodynamic therapy, and immunotherapy for achieving enhanced anticancer effects. Besides, there have also been studies that extend the application of CDT to the antibacterial field. This review introduces the latest advancements in the nanomaterials-involved CDT from 2018 to the present and proposes the current limitations as well as future research directions in the related field.

Tumor microenvironment (TME)-responsive nanosystems represent a category of intelligent nanomaterials for precise anticancer drug delivery. Herein, we report a smart size-/morphology-switchable nanodrug that can respond to the acidic TME and near-infrared (NIR) laser irradiation for effective tumor ablation and tumor metastasis inhibition. The nanoagent is physically assembled by a cytolytic peptide, melittin (MEL), an NIR-absorbing molecule, cypate, and a tumor-targeting polymer, hyaluronic acid (HA). At pH 7.4, the as-formed MEL/Cypate@HA complexes are negatively charged nanospheres (∼50 nm), which are suitable for long-term systemic circulation. When these nanospheres actively target tumors, the weakly acidic TME triggers an

Carbon dots (CDs) are a type of metal-free fluorescent quantum dots and can be synthesized facilely and cost-effectively. In this work, we develop a one-pot solvothermal method to prepare a novel type of quaternized CDs using two commercial reagents (glycerol and dimethyloctadecyl[3-(trimethoxysilyl)propy]ammonium chloride, abbreviated as Si-QAC). The introduction of the long alkyl chain-containing quaternary ammonium compound Si-QAC endows the as-prepared CDs with the capability to interact with the negatively-charged bacterial cells via both electrostatic and hydrophobic interactions. Owning to the different surfaces of Gram-positive and Gram-negative bacteria, the CDs can selectively interact with the Gram-positive bacteria. More interestingly, once the CDs are adsorbed onto the Gram-positive bacteria, their fluorescence emission is significantly enhanced. Furthermore, the CD adsorption can further cause the bacterial cell surface destruction since the CDs may change the charge balance of the bacterial surface and can insert into the bacterial surface via the long alkyl chains, which ultimately leads to the inactivation of Gram-positive bacteria. As compared with the conventional Gram-staining method, the CD-based Gram-type differentiation approach is accurate, fast, and easy-operating. Overall, the quaternized CDs represent a metal-free nanoparticle-based nanotheranostic for imaging-guided bacterial differentiation and inhibition.

Nanomaterial-based enzyme mimics (nanozymes) are attracting increasing attention because of their low production cost, high stability against denaturation, and resistance to high concentrations of substrates. Here, carbon nanoparticles doped with a small amount (

Understanding the self-assembly mechanisms of amphiphilic molecules in solutions and regulating their phase behaviors are of primary significance for their applications. To challenge the reported direct phase transitions from nonlamellar to ordered lamellar phases, the self-assembly and phase behavior of the 1-hexadecyl-3-methylimidazolium chloride aqueous dispersions were studied using a strategy of isothermal incubation after the temperature jump. A disordered lamellar phase (identified as the lamellar liquid-crystal (Lα) phase), serving as an intermediate, was found to bridge the transition from a spherical micellar (M) phase to a lamellar-gel (Lβ) phase. Meanwhile, the nonsynchronicity in the tail and headgroup regions of the ionic liquid surfactant during the transition process was also unveiled, with the former being prior to the latter. The in-depth understanding of the self-assembly mechanisms may help push forward the related applications in the future.

Despite great efforts in the development of diverse nanomaterials, a general route to synthesize metal-free chalcogen quantum dots (QDs) is still lacking. Moreover, the modification of chalcogen QDs is a bottleneck that severely hinders their applications. Herein, we develop a facile method to construct different chalcogen QDs (including S QDs, Se QDs, and Te QDs) with the assistance of thiolates. In addition to stabilizing chalcogen QDs, the thiolates also endow the chalcogen QDs with favorable modifiability. Different from most dyes whose fluorescence is quenched after short-term light irradiation, the prepared chalcogen QDs have significantly enhanced fluorescence emission under continuous light irradiation. Taking advantage of the distinctive photoinduced fluorescence enhancement property, long-time cell imaging with superb performance is realized using the chalcogen QDs. It is envisioned that the chalcogen QDs show promising potential as fluorescent materials in different fields beyond bioimaging. Agency for Science, Technology and Research (A*STAR) National Research Foundation (NRF) This research is supported by the Singapore Agency for Science, Technology and Research (A*STAR) AME IRG grant (A20E5c0081) and the Singapore National Research Foundation Investigatorship (NRF-NRFI2018-03). This work was also supported by the National Natural Science Foundation of China (21673037) and the Fundamental Research Funds for the Central Universities.

The asymmetric distribution of lipids in plasma membranes is closely related to the physiological functions of cells. To improve our previous approach in fabricating asymmetric vesicles, we defined a parameter, asymmetric degree, in this work and investigated the effects of vesicle size, incubation temperature, and lipid composition on the formation process of asymmetric phosphatidylserine (PS)-containing lipid vesicles. The results indicate that all of the three factors have marked but different effects on the time-dependent asymmetric degree of the vesicles as well as the flip and flop rate constants of the PS lipids. However, only vesicle size and PS content show significant influence on the maximal asymmetric degree of the vesicles, while the incubation temperature exhibits negligible effect. This work not only deepens our understanding on the packing property of PS molecules in self-assembled membranes and the formation mechanism of asymmetric vesicles but also practically provides a solution to regulate the asymmetric degree of the PS-containing vesicles using the established kinetic equation. In addition, the method would facilitate researches related to asymmetric vesicles or reconstruction of biological membranes.

Efficient cellular uptake of nanoparticles is crucial for modulating the cell behaviors as well as dictating the cell fate. In this work, by using two commercial reagents (the membrane modification reagent “cholesterol–PEG–biotin” and the avidin-modified quantum dots (QDs) “QD–avidin”), we achieved the enhanced plasma membrane enrichment and endocytosis of fluorescent QDs in cancer cells through cell surface engineering. The QD–cell interaction involved two stages: adsorption and internalization. After incubation with cholesterol–PEG2k–biotin, the cell membrane was engineered with biotin groups that would actively recruit QD–avidin to the cell surface within 1 min. This fast adsorption process could realize high quality and photostable plasma membrane imaging, which is simple, low-cost and generally applicable as compared with the previously reported membrane protein/receptor labeling-based QD imaging. After that, the QDs attached on the cell surface underwent the internalization process and 12 h later, almost all the QDs were internalized through endocytosis. Notably, we found that the internalization of QDs was not via common endocytosis pathways (such as clathrin- or caveolae-mediated endocytosis or macropinocytosis) but more likely via lipid raft-dependent endocytosis. In contrast, without cell surface engineering, the QD–avidin showed negligible cellular uptake. The results demonstrate that cell surface engineering is an efficient strategy to image the plasma membrane and increase cellular uptake of nanoparticles, and will be potentially applied to enhance the efficacy of nanomedicines when therapeutic nanoparticles are used.

The presence of drug efflux pumps and endo/lysosomal entrapment phenomena in multidrug-resistant cancer cells leads to insufficient and off-target accumulation of anticancer drugs in the cells, which severely reduces the drugs' therapeutic efficacies. Here, we prepare a novel type of photosensitizer (PS)-loaded supramolecular nanogel, which can utilize the endo/lysosomal entrapment for enhanced photodynamic therapy (PDT) of multidrug-resistant cancer. The PS-loaded nanogels can elude the drug efflux pumps, and be markedly internalized by drug-resistant cancer cells through the endocytic pathway. With their pH-sensitive properties, the internalized nanogels can aggregate in the acidic endosomes/lysosomes, thus retarding their exocytosis from the cells. Moreover, the lysosomes of the nanogel-treated cells are severely damaged after irradiation, which inhibits the protective autophagy and improves the photodynamic therapeutic performance of the nanogels. Besides, the in vivo experiments show that the nanogels significantly prolong the tumor retention of the PSs, thus enabling multiple PDT treatments after a single drug injection.

Fenton reaction-mediated chemodynamic therapy (CDT) can kill cancer cells via the conversion of H2 O2 to highly toxic HO•. However, problems such as insufficient H2 O2 levels in the tumor tissue and low Fenton reaction efficiency severely limit the performance of CDT. Here, the prodrug tirapazamine (TPZ)-loaded human serum albumin (HSA)-glucose oxidase (GOx) mixture is prepared and modified with a metal-polyphenol network composed of ferric ions (Fe3+ ) and tannic acid (TA), to obtain a self-amplified nanoreactor termed HSA-GOx-TPZ-Fe3+ -TA (HGTFT) for sustainable and cascade cancer therapy with exogenous H2 O2 production and TA-accelerated Fe3+ /Fe2+ conversion. The HGTFT nanoreactor can efficiently convert oxygen into HO• for CDT, consume glucose for starvation therapy, and provide a hypoxic environment for TPZ radical-mediated chemotherapy. Besides, it is revealed that the nanoreactor can significantly elevate the intracellular reactive oxygen species content and hypoxia level, decrease the intracellular glutathione content, and release metal ions in the tumors for metal ion interference therapy (also termed "ion-interference therapy" or "metal ion therapy"). Further, the nanoreactor can also increase the tumor's hypoxia level and efficiently inhibit tumor growth. It is believed that this tumor microenvironment-regulable nanoreactor with sustainable and cascade anticancer performance and excellent biosafety represents an advance in nanomedicine.

In this study, an on-off-on fluorescent nanosensor based on carbon quantum dots (or carbon dots, CDs) was successfully fabricated for Fe3+ detection and selective imaging of cancerous cells in vitro and in vivo. The multifunctional CDs were prepared by a one-pot solvothermal treatment of glycerol and a silane molecule (N-[3-(trimethoxysilyl)propyl]ethylenediamine, DAMO). The as-prepared CDs exhibited excellent fluorescence (FL) properties and favorable biocompatibility, and could realize wash-free cell imaging both in vitro (e.g., for bacterial and fungal cells) and in vivo (e.g., for zebrafish embryos). On the other hand, the fluorescence of CDs can respond to Fe3+ selectively and sensitively, with a very low detection limit of 16 nM. Besides, detection of Fe3+ in living cells and zebrafish was also successfully realized by the CDs. Moreover, it was found that glutathione (GSH) could enhance the fluorescence of the mixed solution of CDs and Fe3+ (CDs/Fe3+), and such a property could be utilized to efficiently distinguish cancerous cells from normal ones based on the difference in the content of GSH of the two types of cells. More importantly, GSH also realized the enhanced fluorescence signals of CDs/Fe3+ in tumor site in vivo after intravenous injection, indicating the potential of CDs/Fe3+ for imaging-guided precision cancer diagnosis.

Theranostic nanoparticles (NPs) capable of mitochondrial targeting/imaging, cancer/normal cell differentiation, early stage cancer diagnosis, and mitochondria-based photothermal therapy (PTT) were developed. The NPs were fabricated by physical encapsulation of near-infrared (NIR) heptamethine cyanine dye me-IR825 into the inner core of the micelle-forming copolymer Pluronic F127 (PF127). The PF127/me-IR825 NPs exhibited two fluorescence emissions at ∼610 nm (excited by 550 nm) and 845 nm (excited by 780 nm). The former was used for in vitro mitochondrial fluorescence imaging, cancer/normal cell differentiation, and early stage cancer detection with high fluorescence contrast. The latter was used for in vivo NIR fluorescence imaging. Besides, the NPs could also be used for in vivo photoacoustic imaging under 808 nm excitation. After irradiation by an 808 nm laser at an elevated power density, the NPs achieved excellent photothermal tumor ablation both in vitro and in vivo. Furthermore, me-IR825 inside the ...

It is of great value to develop new antibacterial photodynamic therapy (PDT) strategies to improve antibacterial PDT efficacy of noncationic photosensitizers without introducing cytotoxicity, which is a great challenge for current leading efforts on antimicrobial PDT based on cell surface engineering. In this research, the hydrophobic and anionic photosensitizer rose bengal (RB) was chemically conjugated with bacterial exopolysaccharide (EPS) to generate an amphiphilic and negatively charged compound EPS-RB that could self-assemble into nanoparticles (NPs) in solution. These EPS-RB NPs possessed an increased singlet oxygen generation property in solution. As a result, EPS-RB exhibited improved photoinactivation for both Gram-negative and Gram-positive bacteria, leading to a record low RB working concentration, 8 μM or 500 nM for Escherichia coli or Staphylococcus aureus, respectively. Upon light irradiation, more EPS-RB bound to the cell surface and penetrated into bacteria than RB, with EPS-RB staying around the cell surface of the most irradiated E. coli while entering all irradiated S. aureus. Both scanning electron microscopy and fluorescence confocal imaging results show that the cell membrane of E. coli was damaged heavily but not S. aureus. All of these observations indicate that both the enhanced singlet oxygen production of EPS-RB NPs in solution and their consequently increased membrane binding and cellular penetration into the bacteria through the damaged cell membrane contribute to their significantly improved bacterial photoinactivation efficiency. In addition, EPS-RB has low cytotoxicity and negligible hemolytic activity, showing great biocompatibility. Therefore, the construction of EPS-RB provides a new strategy for the PDT effectiveness improvement of the separated cell/sensitizer systems and thus the design of next-generation antimicrobial agents.

Nucleolus tracking and nucleus-targeted photodynamic therapy are attracting increasing attention due to the importance of nucleolus and the sensitivity of nucleus to various therapeutic stimuli. Herein, a new class of multifunctional fluorescent carbon quantum dots (or carbon dots, CDs) synthesized via the one-pot hydrothermal reaction of m-phenylenediamine and l-cysteine was reported to effectively target nucleolus. The as-prepared CDs possess superior properties, such as low-cost and facile synthesis, good water dispersibility, various surface groups for further modifications, prominent photostability, excellent compatibility, and rapid/convenient/wash-free staining procedures. Besides, as compared with SYTO RNASelect (a commonly used commercial dye for nucleolus imaging) that can only image nucleolus in fixed cells, the CDs can realize high-quality nucleolus imaging in not only fixed cells but also living cells, allowing the real-time tracking of nucleolus-related biological behaviors. Furthermore, after conjugating with protoporphyrin IX (PpIX), a commonly used photosensitizer, the resultant CD-PpIX nanomissiles showed remarkably increased cellular uptake and nucleus-targeting properties and achieved greatly enhanced phototherapeutic efficiency because the nuclei show poor tolerance to reactive oxygen species produced during the photodynamic therapy. The in vivo experiments revealed that the negatively charged CD-PpIX nanomissiles could rapidly and specifically target a tumor site after intravenous injection and cause efficient tumor ablation with no toxic side effects after laser irradiation. It is believed that the present CD-based nanosystem will hold great potential in nucleolus imaging and nucleus-targeted drug delivery and cancer therapy.

Water-dispersible nanomaterials with superbright photoluminescence (PL) emissions and narrow PL bandwidths are urgently desired for various imaging applications. Herein, for the first time, we prepared ultrasmall organosilica nanodots (OSiNDs) with an average size of ∼2.0 nm and ∼100% green-emitting PL quantum efficiency via a one-step hydrothermal treatment of two commercial reagents (a silane molecule and rose bengal). In particular, the structural reorganization and halide loss of rose bengal during the hydrothermal treatment contribute to the ultrahigh quantum yield and low phototoxicity of OSiNDs. Owing to their low pH-induced precipitation/aggregation property, the as-prepared OSiNDs can be used as excellent lysosomal trackers with many advantages: (1) They have superior lysosomal targeting ability with a Pearson's coefficient of 0.98; (2) The lysosomal monitoring time of OSiNDs is up to 48 h, which is much longer than those of commercial lysosomal trackers (2 h); (3) They do not disturb the pH environment of lysosomes and can be used to visualize lysosomes in living, fixed, and permeabilized cells; (4) They exhibit intrinsic lysosomal tracking ability without the introduction of lysosome-targeting ligands (such as morpholine) and superior photostability; (5) The easy, cost-effective, and scalable synthetic method further ensures that these OSiNDs can be readily used as exceptional lysosomal trackers. We expect that the ultrasmall OSiNDs with superior fluorescence properties and easily modifiable surfaces could be applied as fluorescent nanoprobes, light-emitting diode phosphor, and anticounterfeiting material, which should be able to promote the preparation and application of silicon-containing nanomaterials.

Developing biocompatible and photodegradable photothermal agents (PTAs) holds great promise for potential clinical applications in photothermal cancer therapy. Herein, a new PTA was innovatively constructed by conjugating the hydrophobic near-infrared (NIR) heptamethine cyanine molecule IR825-NH2 with a double hydrophilic block copolymer methoxypoly(ethylene glycol)5k-block-poly(L-aspartic acid sodium salt)10 (abbreviated as PEG-PLD) via amine-carboxyl reaction. The as-designed PEG-PLD(IR825) was amphiphilic and could self-assemble into polymeric nanomicelles in aqueous solutions. Benefiting from the chemical conjugation strategy, PEG-PLD(IR825) nanomicelles realized a considerably high drug loading rate (∼21.0%) and substantially avoided the premature release of IR825 during systemic circulation. Confocal imaging revealed that the nanomicelles mainly located at mitochondria and endoplasmic reticulum after cellular internalization. In vitro photothermal therapy demonstrated the excellent cancer killing efficiency of PEG-PLD(IR825) nanomicelles due to their high light-to-heat conversion efficiency upon NIR laser irradiation. In addition, PEG-PLD(IR825) nanomicelles showed polarity-sensitive fluorescence at ∼610 nm (under 552 nm excitation) and 830 nm (under 780 nm excitation), which was especially useful for both in vitro visible fluorescence imaging and in vivo near-infrared fluorescence imaging-guided photothermal therapy (PTT). At the in vivo level, PEG-PLD(IR825) nanomicelles exhibited an excellent tumor-homing ability and a long retention time in tumor tissues as evidenced by the in vivo fluorescence imaging results. The desirable properties of PEG-PLD(IR825) nanomicelles ensured their effective tumor ablation during PTT treatment. More importantly, the PEG-PLD(IR825) nanomicelles underwent degradation after laser irradiation, which ensured their post-treatment biosafety. Therefore, the nanomicelles are promising to serve as an efficient and safe PTA for imaging-guided photothermal cancer therapy.

Tumor vasculature has long been considered as an extremely valuable therapeutic target for cancer therapy, but how to realize controlled and site-specific drug release in tumor blood vessels remains a huge challenge. Despite the widespread use of nanomaterials in constructing drug delivery systems, they are suboptimal in principle for meeting this demand due to their easy blood cell adsorption/internalization and short lifetime in the systemic circulation. Here, natural red blood cells (RBCs) are repurposed as a remote-controllable drug vehicle, which retains RBC's morphology and vessel-specific biodistribution pattern, by installing photoactivatable molecular triggers on the RBC membrane via covalent conjugation with a finely tuned modification density. The molecular triggers can burst the RBC vehicle under short and mild laser irradiation, leading to a complete and site-specific release of its payloads. This cell-based vehicle is generalized by loading different therapeutic agents including macromolecular thrombin, a blood clotting-inducing enzyme, and a small-molecule hypoxia-activatable chemodrug, tirapazamine. In vivo results demonstrate that the repurposed "anticancer RBCs" exhibit long-term stability in systemic circulation but, when tumors receive laser irradiation, precisely releases their cargoes in tumor vessels for thrombosis-induced starvation therapy and local deoxygenation-enhanced chemotherapy. This study proposes a general strategy for blood vessel-specific drug delivery.

Hydrogels constitute a group of polymeric materials which can hold a large amount of water in their three-dimensional networks due to their hydrophilic structures. In the past few years, they have been researched for various biomedical applications, such as drug/cell carriers, tissue engineering, and biosensors. Particularly, the hydrogels used as drug delivery systems have shown distinct advantages in phototherapy. This review presents recent advancements of hydrogel’s use in phototherapeutic applications by focusing on three kinds of phototherapeutic methods including photodynamic therapy (PDT), photothermal therapy (PTT), and phototherapy-containing combination therapy (PCCT). The applications of these therapies in anticancer and antibacterial fields have also been summarized. We hope that this review will inspire researchers to further develop promising materials for phototherapy applications.

Antibacterial photodynamic therapy (PDT), which enables effective killing of regular and multidrug-resistant (MDR) bacteria, is a promising treatment modality for bacterial infection. However, because most photosensitizer (PS) molecules fail to strongly interact with the surface of Gram-negative bacteria, this technique is suitable for treating only Gram-positive bacterial infection, which largely hampers its practical applications. Herein, we reveal for the first time that cholesterol could significantly facilitate the hydrophobic binding of PSs to the bacterial surface, achieving the hydrophobic interaction-based bacterial cell surface engineering that could effectively photoinactivate both Gram-negative and Gram-positive bacteria. An amphiphilic polymer composed of a polyethylene glycol (PEG) segment terminated with protoporphyrin IX (PpIX, an anionic PS) and cholesterol was constructed (abbreviated Chol-PEG-PpIX), which could self-assemble into micelle-like nanoparticles (NPs) in aqueous solution. When encountering the Gram-negative Escherichia coli cells, the Chol-PEG-PpIX NPs would disassemble and the PpIX moieties could effectively bind to the bacterial surface with the help of the cholesterol moieties, resulting in the significantly enhanced fluorescence emission of the bacterial surface. Under white light irradiation, the light-triggered singlet oxygen (

Carbon nanomaterials have found numerous applications in various fields. However, their synthesis and functionalization usually require complicated procedures or tough experimental conditions. Herein, we report for the first time the synthesis of a new type of functional nanomaterial, quaternized carbon nanospheres (QCNSs), with superior antibacterial activity via a one-pot hydrothermal treatment of chitosan and hexadecylbetaine (abbreviated as BS-16). During the hydrothermal process, the direct reaction and carbonization between the amine-containing chitosan and the carboxyl-containing BS-16 were realized within only one step. The as-prepared QCNSs feature a well-defined spherical morphology and a homogeneous size distribution with an average diameter of ∼110 nm. In particular, the QCNSs could effectively kill Gram-positive bacteria with a minimum inhibitory concentration (MIC) of 2.0-5.0 μg mL-1. Meanwhile, the QCNSs showed excellent cytocompatibility towards normal human liver and lung cells and good hemocompatibility towards red blood cells. Moreover, in bacteria-infected macrophage cells, the QCNSs could selectively kill bacteria while the macrophage cells remained unaffected, which further confirmed their biocompatibility. Besides, we have also elucidated the antibacterial mechanism of the QCNSs by disrupting the bacterial cell walls/membranes via the bacterial adsorption and insertion of the long alkyl chain-containing quaternary ammonium groups on the particle surface. The present work provides a novel method for the preparation of functional carbon nanomaterials, which may promote the development of metal-free antibacterial agents.

Photodynamic therapy is a promising approach for fighting bacterial infections because it can induce few side effects, develop no drug resistance, and realize precise treatment. However, most photosensitizers (PSs) have the disadvantages of poor water-solubility, severe self-quenching, and potential toxicity. Here, the cationic polymer polyethyleneimine (PEI) was used to prepare a cholesterol- and chlorin e6 (Ce6, a common PS)-conjugated compound via the carboxyl-amine reaction or the acyl chloride-amine reaction (abbreviated as Chol-PEI-Ce6). The as-prepared Chol-PEI-Ce6 molecules can self-assemble into close-to-spherical nanoparticles (NPs) with an average diameter of ∼15 nm and can bind to the bacterial surfaces via the synergistic hydrophobic insertion of the cholesterol moieties and electrostatic interaction between the cationic amine groups of PEI and the bacterial surfaces. Upon light irradiation, the NPs can effectively inactivate both Gram-positive and Gram-negative bacteria. Besides, the interaction between Chol-PEI-Ce6 NPs and bacteria markedly enhances the production of intracellular reactive oxygen species after light irradiation, which may account for the excellent antibacterial performance of the NPs. More importantly, the NPs possess negligible dark cytotoxicity and good hemocompatibility. Therefore, the present work may have strong implications for developing novel antibacterial agents to fight against bacterial infections.

Biofilm formation can lead to the treatment failure of persistent bacterial infections. Although a variety of antibacterial agents have been developed, the restricted drug penetration and the embedded bacteria's potentiated recalcitrance to these agents synergistically lead to the unsatisfactory anti-biofilm effect. Herein, we report the applications of metal-free quaternized carbon dots (CDs) in imaging and eliminating bacterial biofilms. The CDs prepared by the solvothermal treatment of dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride (abbreviated as Si-QAC) and glycerol possess ultrasmall size (ca. 3.3 ± 0.4 nm) and strong positively charged (zeta potential: ca. +33.1 ± 2.5 mV) surfaces with long alkyl chain-linked quaternary ammonium groups. The small size of the CDs endows them with the penetration ability into the interior of Gram-negative and Gram-positive bacterial biofilms, which enables excellent fluorescence imaging of the biofilms. Due to the different surfaces of the two types of bacteria, the positively charged CDs selectively interact with the more negatively charged Gram-positive bacteria via electrostatic and hydrophobic interactions, which inactivates the Gram-positive bacteria and ultimately eradicates the Gram-positive bacterial biofilms. In addition, we synthesize a new type of quaternized CDs without long alkyl chains (termed TTPAC CDs), and validate that the long alkyl chains potentiate the hydrophobic adhesion between CDs and Gram-positive bacteria. Meanwhile, the crystal violet staining results reveal that the cationic CDs inhibit the formation of Gram-positive bacterial biofilms. Collectively, our work highlights the feasibility of using cationic and ultrasmall metal-free CDs to eliminate and inhibit Gram-positive bacterial biofilms, which represents a highly effective strategy to cope with refractory biofilm-associated infections.

Red-emitting carbon dots (CDs) have attracted tremendous attention due to their wide applications in areas including imaging, sensing, drug delivery, and cancer therapy. However, it is still highly challenging for red-emitting CDs to simultaneously achieve high quantum yields (QYs), nucleus targeting, and super-resolution fluorescence imaging (especially the stimulated emission depletion (STED) imaging). Here, it is found that the addition of varied metal ions during the hydrothermal treatment of

Polyphenols, the phenolic hydroxyl group-containing organic molecules, are widely found in natural plants and have shown beneficial effects on human health. Recently, polyphenol-containing nanoparticles have attracted extensive research attention due to their antioxidation property, anticancer activity, and universal adherent affinity, and thus have shown great promise in the preparation, stabilization, and modification of multifunctional nanoassemblies for bioimaging, therapeutic delivery, and other biomedical applications. Additionally, the metal-polyphenol networks, formed by the coordination interactions between polyphenols and metal ions, have been used to prepare an important class of polyphenol-containing nanoparticles for surface modification, bioimaging, drug delivery, and disease treatments. By focusing on the interactions between polyphenols and different materials (e.g., metal ions, inorganic materials, polymers, proteins, and nucleic acids), a comprehensive review on the synthesis and properties of the polyphenol-containing nanoparticles is provided. Moreover, the remarkable versatility of polyphenol-containing nanoparticles in different biomedical applications, including biodetection, multimodal bioimaging, protein and gene delivery, bone repair, antibiosis, and cancer theranostics is also demonstrated. Finally, the challenges faced by future research regarding the polyphenol-containing nanoparticles are discussed.

In this work, we prepared quaternized carbon dots (CDs) with simultaneous antibacterial and bacterial differentiation capabilities using a simple carboxyl-amine reaction between lauryl betaine and amine-functionalized CDs. The obtained quaternized CDs have several fascinating properties/abilities: (1) A long fluorescence emission wavelength ensures the exceptional bacterial imaging capability, including the super-resolution imaging ability; (2) the polarity-sensitive fluorescence emission property leads to significantly enhanced fluorescence when the quaternized CDs interact with bacteria; (3) the presence of both hydrophobic hydrocarbon chains and positively charged quaternary ammonium groups makes the CDs selectively attach to Gram-positive bacteria, realizing the bacterial differentiation; (4) excellent antimicrobial activity is seen against Gram-positive bacteria with a minimum inhibitory concentration of 8 μg/mL for Staphylococcus aureus. Besides, the quaternized CDs are highly stable in various aqueous solutions and exhibit negligible cytotoxicity, suggesting that they hold great promise for clinical applications. Compared to the traditional Gram staining method, the selective Gram-positive bacterial imaging achieved by the quaternized CDs provides a much simpler and faster method for bacterial differentiation. In summary, by combining selective Gram-positive bacterial recognition, super-resolution imaging, and exceptional antibacterial activity into a single system, the quaternized CDs represent a novel kind of metal-free nanoparticle-based antibiotics for antibacterial application and a new type of reagent for efficient bacterial differentiation.

Metallic nanostructures as excellent candidates for nanosensitizers have shown enormous potentials in cancer radiotherapy and photothermal therapy. Clinically, a relatively low and safe radiation dose is highly desired to avoid damage to normal tissues. Therefore, the synergistic effect of the low-dosed X-ray radiation and other therapeutic approaches (or so-called "combined therapeutic strategy") is needed. Herein, we have synthesized hollow and spike-like gold nanostructures by a facile galvanic replacement reaction. Such gold nanospikes (GNSs) with low cytotoxicity exhibited high photothermal conversion efficiency (η = 50.3%) and had excellent photostability under cyclic near-infrared (NIR) laser irradiations. We have demonstrated that these GNSs can be successfully used for in vitro and in vivo X-ray radiation therapy and NIR photothermal therapy. For the in vitro study, colony formation assay clearly demonstrated that GNS-mediated photothermal therapy and X-ray radiotherapy reduced the cell survival fraction to 89% and 51%, respectively. In contrast, the cell survival fraction of the combined radio- and photothermal treatment decreased to 33%. The synergistic cancer treatment performance was attributable to the effect of hyperthermia, which efficiently enhanced the radiosensitizing effect of hypoxic cancer cells that were resistant to ionizing radiation. The sensitization enhancement ratio (SER) of GNSs alone was calculated to be about 1.38, which increased to 1.63 when the GNS treatment was combined with the NIR irradiation, confirming that GNSs are effective radiation sensitizers to enhance X-ray radiation effect through hyperpyrexia. In vivo tumor growth study indicated that the tumor growth inhibition (TGI) in the synergistically treated group reached 92.2%, which was much higher than that of the group treated with the GNS-enhanced X-ray radiation (TGI = 29.8%) or the group treated with the GNS-mediated photothermal therapy (TGI = 70.5%). This research provides a new method to employ GNSs as multifunctional nanosensitizers for synergistic NIR photothermal and X-ray radiation therapy in vitro and in vivo.

Cholesterol-containing molecules or nanoparticles play a significant role in achieving favorable plasma membrane imaging and efficient cellular uptake of drugs by the excellent membrane anchoring capability of the cholesterol moiety. By linking cholesterol to a water-soluble component (such as poly(ethylene glycol), PEG), the resulting cholesterol-PEG conjugate can form micelles in aqueous solution through self-assembly, and such a micellar structure represents an important drug delivery vehicle in which hydrophobic drugs can be encapsulated. However, the understanding of the subcellular fate and cytotoxicity of cholesterol-PEG conjugates themselves remains elusive. Herein, by using cholesterol-PEG2000-fluorescein isothiocyanate (Chol-PEG-FITC) as a model system, we found that the Chol-PEG-FITC molecules could attach to the plasma membranes of mammalian cells within 10 min and such a firm membrane attachment could last at least 1 h, displaying excellent plasma membrane staining performance that surpassed that of commonly used commercial membrane dyes such as DiD and CellMask. Besides, we systematically studied the endocytosis pathway and intracellular distribution of Chol-PEG-FITC and found that the cell surface adsorption and endocytosis processes of Chol-PEG-FITC molecules were lipid-raft-dependent. After internalization, the Chol-PEG-FITC molecules gradually reached many organelles with membrane structures. At 5 h, they were mainly distributed in lysosomes and the Golgi apparatus, with some in the endoplasmic reticulum (ER) and very few in the mitochondrion. At 12 h, the Chol-PEG-FITC molecules mostly aggregated in the Golgi apparatus and ER close to the nucleus. Finally, we demonstrated that Chol-PEG-FITC was toxic to mammalian cells only at concentrations above 50 μM. In summary, Chol-PEG-FITC can be a promising plasma membrane imaging reagent to avoid the fast cellular internalization and quick membrane detachment problems faced by commercial membrane dyes. We believe that the investigation of the dynamic subcellular fate of Chol-PEG-FITC can provide important knowledge to facilitate the use of cholesterol-PEG conjugates in fields such as cell surface engineering and drug delivery.

Lipid rafts are highly ordered small microdomains mainly composed of glycosphingolipids, cholesterol, and protein receptors. Optically distinguishing lipid raft domains in cell membranes would greatly facilitate the investigations on the structure and dynamics of raft-related cellular behaviors, such as signal transduction, membrane transport (endocytosis), adhesion, and motility. However, current strategies about the visualization of lipid raft domains usually suffer from the low biocompatibility of the probes, invasive detection, or ex situ observation. At the same time, naturally derived biomacromolecules have been extensively used in biomedical field and their interaction with cells remains a long-standing topic since it is closely related to various fundamental studies and potential applications. Herein, noninvasive visualization of lipid raft domains in model lipid bilayers (supported lipid bilayers and giant unilamellar vesicles) and live cells was successfully realized in situ using fluorescent biomacromolecules: the fluorescein isothiocyanate (FITC)-labeled glycol chitosan molecules. We found that the lipid raft domains in model or real membranes could be specifically stained by the FITC-labeled glycol chitosan molecules, which could be attributed to the electrostatic attractive interaction and/or hydrophobic interaction between the probes and the lipid raft domains. Since the FITC-labeled glycol chitosan molecules do not need to completely insert into the lipid bilayer and will not disturb the organization of lipids, they can more accurately visualize the raft domains as compared with other fluorescent dyes that need to be premixed with the various lipid molecules prior to the fabrication of model membranes. Furthermore, the FITC-labeled glycol chitosan molecules were found to be able to resist cellular internalization and could successfully visualize rafts in live cells. The present work provides a new way to achieve the imaging of lipid rafts and also sheds new light on the interaction between biomacromolecules and lipid membranes.

The folding/unfolding behavior of proteins (enzymes) in confined space is important for their properties and functions, but such a behavior remains largely unexplored. In this article, we reported our finding that lysozyme and a double hydrophilic block copolymer, methoxypoly(ethylene glycol)5K-block-poly(l-aspartic acid sodium salt)10 (mPEG(5K)-b-PLD10), can form a polyelectrolyte complex micelle with a particle size of ∼30 nm, as verified by dynamic light scattering and transmission electron microscopy. The unfolding and refolding behaviors of lysozyme molecules in the presence of the copolymer were studied by microcalorimetry and circular dichroism spectroscopy. Upon complex formation with mPEG(5K)-b-PLD10, lysozyme changed from its initial native state to a new partially unfolded state. Compared with its native state, this copolymer-complexed new folding state of lysozyme has different secondary and tertiary structures, a decreased thermostability, and significantly altered unfolding/refolding behaviors. It was found that the native lysozyme exhibited reversible unfolding and refolding upon heating and subsequent cooling, while lysozyme in the new folding state (complexed with the oppositely charged PLD segments of the polymer) could unfold upon heating but could not refold upon subsequent cooling. By employing the heating-cooling-reheating procedure, the prevention of complex formation between lysozyme and polymer due to the salt screening effect was observed, and the resulting uncomplexed lysozyme regained its proper unfolding and refolding abilities upon heating and subsequent cooling. Besides, we also pointed out the important role the length of the PLD segment played during the formation of micelles and the monodispersity of the formed micelles. Furthermore, the lysozyme-mPEG(5K)-b-PLD10 mixtures prepared in this work were all transparent, without the formation of large aggregates or precipitates in solution as frequently observed in other protein-polyelectrolyte systems. Hence, the present protein-PEGylated poly(amino acid) mixture provides an ideal water-soluble model system to study the important role of electrostatic interaction in the complexation between proteins and polymers, leading to important new knowledge on the protein-polymer interactions. Moreover, the polyelectrolyte complex micelle formed between protein and PEGylated polymer may provide a good drug delivery vehicle for therapeutic proteins.

Herein, water-dispersible carbon nano-onion clusters (CNOCs) with an average hydrodynamic size of ≈90 nm are prepared by simply sonicating candle soot in a mixture of oxidizing acid. The obtained CNOCs have high photothermal conversion efficiency (57.5%), excellent aqueous dispersibility (stable in water for more than a year without precipitation), and benign biocompatibility. After polyethylenimine (PEI) and poly(ethylene glycol) (PEG) modification, the resultant CNOCs-PEI-PEG have a high photothermal conversion efficiency (56.5%), and can realize after-wash photothermal cancer cell ablation due to their ultrahigh cellular uptake (21.3 pg/cell), which is highly beneficial for the selective ablation of cancer cells via light-triggered intracellular heat generation. More interestingly, the cellular uptake of CNOCs-PEI-PEG is so high that the internalized nanoagents can be directly observed under a microscope without fluorescent labeling. Besides, in vivo experiments reveal that CNOCs-PEI-PEG can be used for photothermal/photoacoustic dual-modal imaging-guided photothermal therapy after intravenous administration. Furthermore, CNOCs-PEI-PEG can be efficiently cleared from the mouse body within a week, ensuring their excellent long-term biosafety. To the best of the authors' knowledge, the first example of using candle soot as raw material to prepare water-dispersible onion-like carbon nanomaterials for cancer theranostics is represented herein.