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Self-targeting antimicrobial platforms have yielded new possibilities for the treatment of infectious biofilms. Self-targeting involves stealth transport through the blood circulation towards an infectious biofilm, where the antimicrobial platform penetrates and accumulates in a biofilm in response to a change in environmental conditions, such as local pH. In a final step, nano-antimicrobials need to be activated or the antimicrobial cargo of nanocarriers released. Zwitterions possess both cationic and anionic groups, allowing full reversal in zeta potential from below to above zero in response to a change in environmental conditions. Electrolyte-based platforms generally do not have the ability to change their zeta potentials from below to above zero. Zwitterions for use in self-targeting platforms are usually hydrophilic and have a negative charge under physiological conditions (pH 7.4) providing low adsorption of proteins and assisting blood circulation. However, near or in the acidic environment of a biofilm, they become positively-charged yielding targeting, penetration and accumulation in the biofilm through electrostatic double-layer attraction to negatively-charged bacteria. Response-times to pH changes vary, depending on the way the zwitterion or electrolyte is built in a platform. Self-targeting zwitterion-based platforms with a short response-time in vitro yield different accumulation kinetics in abdominal biofilms in living mice than platforms with a longer response-time. In vivo experiments in mice also proved that self-targeting, pH-responsive zwitterion-based platforms provide a feasible approach for clinical control of bacterial infections. Clinically however, also other conditions than infection may yield an acidic environment. Therefore, it remains to be seen whether pH is a sufficiently unique recognition sign to direct self-targeting platforms to an infectious biofilm or whether (additional) external targeting through e.g. near-infrared irradiation or magnetic field application is needed.

In the past ten years, photothermal therapy (PTT) has attracted widespread attention in tumor treatment due to its non-invasiveness and little side effects. PTT utilizes heat produced by photothermal agents under the irradiation of near-infrared light to kill tumor cells. Boron-dipyrromethene (BODIPY), an organic phototherapy agent, has been widely used in tumor phototherapy due to its higher molar extinction coefficient, robust photostability and good phototherapy effect. However, there are some issues in the application of BODIPY for tumor PTT, such as low photothermal conversion efficiency and short absorption wavelength. In this review, we focus on the latest development of BODIPY nanomaterials for overcoming the above problems and enhancing the PTT effect.

In this paper, MPDA@hydroxyapatite nanocomposites (MPHA NCs) were prepared and applied to develop a novel reactive oxygen species (ROS)-triggered nitric oxide (NO)-enhanced photothermal therapy nanocomposite system composed of indocyanine green (ICG)/L-arginine-MPDA@HAp (AI-MPHA NCs) for displaying both NO gas therapy and photothermal osteosarcoma treatment. The nanosystem exhibited a mesoporous and core-shell structure and high ICG loading efficiency (about 90%). Under near infrared (NIR) irradiation, the AI-MPHA NCs could not only produce heat but also generate reactive oxygen species (ROS), inducing the catalysis of L-Arg to obtain NO. Under NIR irradiation, the AI-MPHA NCs achieved osteosarcoma ablation by a synergistic combination of photothermal therapy and NO-gas therapy. Additionally, the cell viability of MG-63 cells decreased to 23.6% (co-incubated with AI-MPHA NCs) under irradiation with a power density at 1.0 W cm-2 for 10 min. The study proposed a novel nano-platform for NO-enhanced photothermal therapy of osteosarcoma.

Tumor tissues are not only independent of cancer cells, but also tumor blood vessels. Thus, targeting the tumor blood vessels is as important as targeting the tumor for cancer treatment. Herein, an organic semiconducting molecule named T8IC is developed for the potential phototeranostics in the second near-infrared window (NIR-II, 1000-1700 nm). The T8IC molecule with an electronic-rich core and electron-deficient side edge shows a typical semiconducting structure, which makes the bandgap narrow. With the addition of anti-angiogenic agent sorafenib into T8IC, TS nanoparticles (NPs) were formed by nanoprecipitation with synergetic anti-angiogenic and phototheranostic effects. Compared to the molecular state, the J-aggregative TS NPs were formed with great bathochromic-shifts in both the absorption spectrum (maximum increased from 755 nm to 826 nm) and the emission spectrum (maximum increased from 840 nm to 1030 nm), which endow them with the ideal deep tumor NIR-II fluorescence imaging ability. Besides, TS NPs present both high photothermal conversion efficiency (∼32.47%) and good ROS generation ability, making them possess excellent cancer phototherapy capability. Guided by NIR-II fluorescence imaging, the tumor blood vessels can be cut off via sorafenib and cancer cells can be killed via T8IC simultaneously, making TS NPs show promising potential for the synergistic therapeutic effect in clinical applications.

Featuring simultaneous multicolor imaging for multiple targets, a synergistic strategy has become promising for fluorescence imaging applications. Visible and first near infrared (NIR-I, 700–900 nm) fluorophores have been explored for multicolor imaging to achieve good multi-target capacity, but they are largely hampered by the narrow imaging bands available (400–900 nm, bandwidth 500 nm), the broad emission spectra of many fluorophores, shallow tissue penetration and scattering loss. With attractive characteristic emission peaks in the second NIR window (NIR-II, 1000–1700 nm), a narrow emission spectrum, and deeper tissue penetration capability, rare-earth doped nanoparticles (RENPs) have been considered by us to be outstanding candidates for multicolor bioimaging. Herein, two RENPs, NaYF4:Yb20Er2@NaYF4 and NaYF4:Nd5@NaYF4, were prepared and modified with polyethylene glycol (PEG) to explore simultaneous imaging in the NIR-IIb (1530 nm, under 980 nm laser excitation) and the NIR-II (1060 nm, under 808 nm laser excitation) windows. The PEGylated-RENPs (RENPs@PEG) were able to simultaneously visualize the circulatory system, trace the lymphatic system, and evaluate the skeletal system. Our study demonstrates that RENPs have high synergistic imaging capability in multifunctional biomedical applications using their NIR-II fluorescence. Importantly, the two RENPs@PEG are complementary to each other for higher temporal resolution in NaYF4:Nd5@NaYF4@PEG and higher spatial resolution in NaYF4:Yb20Er2@NaYF4@PEG, which may provide more comprehensive and accurate imaging diagnosis. In conclusion, RENPs are highly promising nanomaterials for multicolor imaging in the NIR-II window.

Mitochondrial proteins, most of which are encoded in the nucleus and the rest of which are regulated by the mitochondrial genome, play pivotal roles in essential cellular functions. However, fluorescent probes that can be used for monitoring mitochondrial proteins have not yet been widely developed, thereby severely limiting the exploration of the functions of proteins in mitochondria. Towards this end, here we propose a near-infrared (NIR) fluorescence probe MPP to effectively illuminate the dynamic changes in mitochondrial proteins in live cells under oxidative stress, with excellent temporal and spatial resolution. Of particular importance, MPP extends the study of the pharmacology involved in apoptosis induced by anti-cancer drugs (hydroxycamptothecin (HCPT), epirubicin (Epi) and cyclophosphamide (CPA)) for the first time. Furthermore, employing a protein-activatable strategy, this probe could serve as an excellent phototherapeutic agent in photodynamic therapy (PDT). Finally, in vivo experiments suggest that this versatile probe can be used to image tumors in HeLa tumor-bearing mice for 24 h, which demonstrates that our probe could play a dual role as a robust phototherapeutic and imaging agent.

Light has been present throughout the history of mankind and even the universe. It is of great significance to human life, contributing to energy, agriculture, communication, and much more. In the biomedical field, light has been developed as a switch to control medical processes with minimal invasion and high spatiotemporal selectivity. During the past three years, near-infrared (NIR) light as long-wavelength light has been applied to more than 3000 achievements in biological applications due to its deep penetration depth and low phototoxicity. Remotely controlled cancer therapy usually involves the conversion of biologically inert NIR light. Thus, various materials, especially nanomaterials that can generate reactive oxygen species (ROS), ultraviolet (UV)/visual light, or thermal energy and so on under NIR illumination achieve great potential for the research of nanomedicine. Here, we offered an overview of recent advances in NIR light-activated nanomedicine for cancer therapeutic applications. NIR-light-conversion nanotechnologies for both directly triggering nanodrugs and smart drug delivery toward tumor therapy were discussed emphatically. The challenges and future trends of the use of NIR light in biomedical applications were also provided as a conclusion. We expect that this review will spark inspiration for biologists, materials scientists, pharmacologists, and chemists to fight against diseases and boost the future clinical-translational applications of NIR technology-based precision nanomedicine.

To achieve accurate fluorescence imaging-guided cancer therapy, intelligent systems with specific responsiveness to the tumor microenvironment need to be designed. Here, we have achieved both enhanced NIR fluorescence and photodynamic therapy by introducing a dimethylamino functional group in BODIPY dyes, which can be used as a pH sensor under acidic conditions by coordinating with the proton. At pH 7.4, the fluorescence is quenched due to the photo-induced electron transfer (PET) process. After the photosensitizer is protonated in tumor cell lysosomes (pH 4.0-5.5), the PET process is inhibited and the fluorophore emission capacity is restored (fluorescence enhancement up to 10-fold), resulting in near-infrared fluorescence with the OFF/ON transition inside the tumor and enhanced singlet oxygen production for lysosome targeting capability. Due to the substitution of heavy atom iodine, the compound has a high singlet oxygen quantum yield of 81.8% in dichloromethane. In addition, using a pH-sensitive amphiphilic polypeptide (POEGMA23-PE9) as a carrier to wrap the photosensitizer BDPI can release enough drug in the acidic environment (pH 5.5-6.5) of intracellular endosomes/lysosomes, which is conducive to more adequate interactions of the photosensitizer with H+ and more effective enhancement of fluorescence emission and 1O2 production, achieving precise fluorescence imaging capability and extremely low background toxicity.

Skin necrosis is the most serious complication of flap plastic surgery, which means the failure of the operation. Systemic administration rarely benefits the local area and can lead to side effects, while topical administration has poor permeability due to the skin barrier function. Currently, few of these common medical interventions can totally respond to the blood supply of the skin after surgery. Herein, a soluble microneedle (MN) patch made of hyaluronic acid was used to target the ischemic area in a painless and precise manner for transdermal drug delivery. Based on the important role of nitric oxide (NO) in angiogenesis, the thermosensitive NO donor (BNN6) and gold nanorods (GNRs) acting as photothermal agents were introduced into the microneedles (MNs). The hyperthermia induced by GNRs under near infrared (NIR, 808 nm) irradiation could enhance the penetration of drugs and facilitate NO release from BNN6. A series of corresponding experiments proved that the system played a significant promotion role in vascular regeneration, providing a painless, precise and NO-assisted treatment method for the ischemic perforator flaps.

The second near-infrared biological window b (NIR-IIb, 1500-1700 nm) is recently considered as the promising region for deeper tissue penetration. Herein, a nanocarrier for 1550 nm light-responsive dual-photodynamic therapy (PDT) is developed to efficiently boost singlet oxygen (1O2) generation. The dual-photosensitizers (PSs), rose bengal (RB) and chlorin e6 (Ce6), are carried by the silica-coated core-shell LiYbF4:Er@LiGdF4 upconversion nanoparticles (UCNPs), forming UCNP/RB,Ce6. Following 1550 nm laser irradiation, the upconversion emission of UCNP/RB,Ce6 in both green (∼550 nm) and red (∼670 nm) colors is fully utilized to activate RB and Ce6, respectively. The simultaneous triggering of dual-PS generates an abundant amount of 1O2 resulting in boosted PDT efficacy. This dual-PDT nanocarrier presents an enhanced anticancer effect under single dose treatment in comparison with the single-PS ones from in vitro and in vivo treatments. The marriage between the boosted dual-PDT and 1550 nm light excitation is anticipated to provide a new avenue for non-invasive therapy.

A near-infrared reactive cyanine platform (probe A) was prepared by condensation of 9-chloro-1,2,3,4-tetrahydro-10-methyl-acridinium iodide with Fisher’s aldehyde. A near-infrared fluorescent probe (probe B) was prepared by modifying a reactive chlorine atom of probe A with tert-butyl(2-aminoethyl)carbamate through a substitution reaction. The deprotection of the Boc group of probe B was achieved under an acidic condition, affording an amine-functionalized cyanine dye (probe C). A near-infrared ratiometric fluorescent probe (probe D) for mitochondrial pH detection was synthesized by conjugating a FRET coumarin donor to a FRET cyanine acceptor (probe C) through an amide bond connection. Probe A shows low fluorescence of 2% due to an electron-withdrawing chlorine atom, while probes B–D display high fluorescence quantum yields of 60%, 32%, and 35% in aqueous solutions containing 10% ethanol, respectively. Probes B–D show strong fluorescence with push–pull molecular structures in neutral and basic pH conditions. However, protonation of the probe’s second amine at the 9-position under acidic condition disrupts the push–pull feature of the probes, resulting in fluorescence quenching of the new cyanine fluorophores. The probes can selectively stain mitochondria, while probe D was employed to detect pH changes in HeLa cells and Drosophila melanogaster first-instar larvae.

Alzheimer's disease (AD) is an incurable neurodegenerative disease. Repairing damaged nerves and promoting nerve regeneration are key ways to relieve AD symptoms. However, due to the lack of effective strategies to deliver nerve growth factor (NGF) to the brain, achieving neuron regeneration is a major challenge for curing AD. Herein, a ROS-responsive ruthenium nanoplatform (R@NGF-Se-Se-Ru) drug delivery system for AD management by promoting neuron regeneration and Aβ clearance was investigated. Under near-infrared (NIR) irradiation, nanoclusters have good photothermal properties, which can effectively inhibit the aggregation of Aβ and disaggregate Aβ fibrils. Interestingly, the diselenide bond in the nanoclusters is broken, and the nanoclusters are degraded into small ruthenium nanoparticles in the high reactive oxygen species (ROS) environment of the diseased area. Besides, NGF can promote neuronal regeneration and repair damaged nerves. Furthermore, R@NGF-Se-Se-Ru efficiently crosses the blood-brain barrier (BBB) owing to the covalently grafted target peptides of RVG (R). In vivo studies demonstrate that R@NGF-Se-Se-Ru nanoclusters decrease Aβ deposits, inhibit Aβ-induced cytotoxicity, and promote neurite outgrowth. The study confirms that promoting both Aβ clearance and neuron regeneration is an important therapeutic target for anti-AD drugs and provides a novel insight for AD therapy.

1T-phase niobium telluride (NbTe2) nanosheets are becoming increasingly important in emerging fields, such as spintronics, sensors and magneto-optoelectronics, due to their excellent physical and chemical properties. However, exploration on their biomedical applications are limited. Herein, ultrathin 1T-phase NbTe2 single-crystalline nanosheets with excellent photothermal performance, high drug-loading rate, near-infrared (NIR) light/acidic pH-triggered drug release, and low toxicity were developed for potentiated photothermal therapy. Importantly, they showed excellent biocompatibility in vivo and in vitro. NbTe2 nanosheets loaded with integrated stress response inhibitors (ISRIB) could achieve chemo-photothermal therapy of tumors through the ATF4-ASNS signaling axis. Ultrathin 1T-phase NbTe2 single-crystalline nanosheets with unique photothermal properties, drug loading rate and safety provide dramatic possibilities in biomedical applications, such as tissue imaging, photothermal therapeutics and pharmaceutics.

Photothermal therapy (PTT) has been widely applied in cancer therapy as a result of its non-invasive, localized treatment and good therapeutic effect. In general, the final therapeutic effect of PTT mainly depends on the photothermal materials, which can be further considered to be determined by the photothermal conversion efficiency, biocompatibility, and photothermal stability of photothermal materials. In this review, photothermal materials including inorganic materials, organic materials, and organic-inorganic composite materials in recent years have been summarized in terms of the mechanism, preparation, and cancer therapy applications. In the end, the perspectives and obstacles in their further development are overviewed.

Non-chemotherapeutic tumour treatment has received extensive attention due to its having fewer side effects as compared to chemotherapy. However, nanomaterials-based non-chemotherapy still faces limitations such as poor targeting and low retention. Therefore, a Schiff base cross-linked hydrogel was designed and prepared using aldehyde-modified polyethylene glycol (PEG) and carboxymethyl chitosan (CMC). This hydrogel has good injectable and self-healing properties and can carry graphene oxide (GO) as a photothermal agent and needle-like nano-hydroxyapatite (HAP) as a tumour inhibitor. Combined with tumour proliferation inhibition therapy and photothermal therapy, the nanocomposite hydrogel system can avoid the side effects of chemotherapy and improve the accuracy of tumour treatment. The PEG–CMC/HAP/GO nanocomposite hydrogel system has a porous structure, good injectability and self-healing properties to meet the mechanical requirements. In vitro cell characterization showed that GO is phototoxic to tumour cells, HAP can inhibit the proliferation of tumour cells, the nanocomposite hydrogel remained in the tumour site, and the encapsulated GO and HAP did not transfer to the normal site and cause cell damage. In the in vivo investigation, the breast cancer tumour-bearing mice, the model animals for tumour treatment, were treated with an intratumoral injection of the PEG–CMC/HAP/GO nanocomposite hydrogel. This functional self-healing hydrogel loaded with GO and HAP effectively inhibited tumour cell proliferation and realized the synergistic effect of photothermal therapy, which is expected to become a new effective treatment approach for tumours.

A novel hybrid drug carrier has been designed, taking N-doped mesoporous carbon (NMCS) as the core and PEG-PEI as the outer shell. NMCS was functionalized with a photocleavable nitrobenzyl-based linker following a click reaction. Gemcitabine was loaded into NMCS prior to the functionalization via π-π stacking interactions. NIR and the pH-responsive behavior of NMCS-linker-PEG-PEI bestow the multifunctional drug carrier with the controlled release of gemcitabine triggered by dual stimuli. The NMCS core upconverts NIR light to UV, which is absorbed by a photosensitive molecular gate and results in its cleavage and drug release. Further, NMCS converts NIR to heat, which deforms the outside polymer shell, thus triggering the drug release process. The release can be promptly arrested if the NIR source is switched off. A promising gemcitabine release of 75% has been achieved within 24 h under the dual stimuli of pH and temperature. NMCS-linker-PEG-PEI produced reactive oxygen species (ROS), which were verified in FaDu cells using flow cytometry. In vitro experiments showed that the NMCS-linker-PEG-PEI-GEM hybrid particle can induce synergistic therapeutic effects in FADU cells when exposed to the NIR light.

It is of great significance to find effective thrombolytic treatments due to the harm caused by thrombosis to human health. Based on the formation mechanism and complex microenvironment of a thrombus, polydopamine nanomotors (PDANMs) modified by the peptide of Arg-Gly-Asp (RGD) and loaded with urokinase (UK) were designed and prepared. A polydopamine (PDA) substrate has a good photothermal conversion effect. Under near-infrared (NIR) light irradiation, it can not only perform photothermal therapy (PTT) on thrombus, but also provide the driving force of PDANMs. Thrombolytic drug UK was loaded in the mesoporous structure of the PDA substrate and can be released at the thrombus site for drug therapy. The modified RGD can target the thrombus site, moreover, benefiting from the guanidine group of L-arginine in the peptide chain, and RGD can interact with reactive oxygen species (ROS) in the thrombus microenvironment to produce nitric oxide (NO). NO not only propelled the movement of nanomotors, but also promoted the growth of vascular endothelial cells to repair damaged blood vessels. The experimental results show that NIR and NO can provide dual driving sources for the nanosystem to achieve continuous and deep penetration of the drug-loaded nanomotors at the thrombus site, while realizing the photothermal and drug synergistic therapy to enhance the therapeutic effect and promote the growth of vascular endothelium cells. This kind of thrombus treatment strategy based on nanomotor drug delivery systems will provide good technical support for the clinical treatment of inferior vena cava thrombus.

Programmable and reconfigurable artificial muscles are highly promising and desirable for applications in various fields, including soft robotics, flexible devices, and biomedical devices. However, the combination of considerable strain and high energy density remains a dilemma to overcome. As stimulus-responsive polymers, shape memory polymers (SMPs) with enhanced mechanical properties and programmability have the potential to solve this problem. However, the purest shape memory polymer lacks reconfigurability, and it is challenging to achieve precise control due to its intrinsic thermal stimulation. Herein, we report a novel reconfigurable multi-block shape memory polymer and its composite with a granular micro-phase separated structure. The polymer demonstrated outstanding artificial muscle performance through the energy storing and releasing method, whose energy density and strain reached 717.8 kJ m-3 and 947%, respectively (17.9 and 23.7 times higher than that of mammalian skeletal muscles). Moreover, by incorporating Fe3O4 nanoparticle (Fe3O4 NP) photothermal transducers, the composite could achieve contraction, reversible muscle-like bending and complex programmable and reconfigurable deformation under near-infrared laser irradiation, including deformation into a specific letter shape, precise origami and bending with loads. Therefore, the prepared materials have excellent prospects as artificial muscles and high-power actuators for broad applications.

Gold nanoparticles (AuNPs) were surface-engineered with a cationic corona to enhance the incorporation of photosensitizers for photodynamic therapy (PDT). The cationic corona composed of poly(2-(dimethylamino)ethyl methacrylate) was atom transfer radical-polymerized on the surface of the AuNPs. The cationic corona of the engineered surface was characterized by dynamic light scattering, electron microscopy, Raman spectroscopy, and mass spectroscopy. Chlorin-e6 (Ce6) incorporated onto the surface-engineered AuNPs exhibited higher cell incorporation efficiency than bare AuNPs. Ce6-incorporated AuNPs were confirmed to release singlet oxygen upon NIR irradiation. Compared to Ce6, Ce6-incorporated AuNPs exhibited higher cellular uptake and cytotoxicity against cancer cells in an irradiation time-dependent manner. Near-infrared-irradiated animals administered Ce6-incorporated AuNPs exhibited higher levels of tumor suppression without noticeable body weight loss. This result was attributed to the higher localization of Ce6 at the tumor sites to induce cancer cell apoptosis. Thus, we envision that engineered AuNPs with cationic corona can be tailored to effectively deliver photosensitizers to tumor sites for photodynamic therapy.

Tumor-targeting gold nanorods (AuNRs) assembled through Au-S bonds have been widely used for photothermal therapy (PTT) via intravenous injection. However, with extended in vivo circulation times, biothiols can replace some S-modified targeting ligands on the surface of the AuNRs, which lowers their targeting efficacy towards cancer cells, resulting in a non-ideal PTT effect. To address this problem, herein, we utilized Se-modified AuNRs to establish a dual functional nanoprobe (Casp-RGD-Se-AuNRs) for improving the therapeutic effect and real-time monitoring of Caspase-9 levels to indicate the degree of cell apoptosis. The experiments demonstrated that the Casp-RGD-Se-AuNRs are better at avoiding interference from biothiols than the S-modified nanoprobe (Casp-RGD-S-AuNRs) for extended blood-circulation times after intravenous injection, significantly improving the PTT efficacy via more effectively targeting cancer cells. Simultaneously, the change of Caspase-9 levels visually shows the degree of apoptosis. Moreover, an in vivo study showed that, compared with the S-modified nanoprobe, the Se-modified nanoprobe exhibits a higher delivery efficiency to the tumor region after intravenous injection (accumulation in the tumor increased by 87%) and a better anticancer efficacy under NIR light irradiation (the tumor inhibition rate increased 6-fold). This work provides a valuable strategy to overcome the off-target problem, and new ideas for avoiding interference by biomolecules during blood circulation.

The overexpression of P-glycoprotein (P-gp) in multidrug resistance (MDR) cancer cells increases the efflux of anticancer drugs thereby causing the failure of clinical chemotherapy. To address this obstacle, in this study, we rationally designed a near-infrared (NIR) light-responsive nitric oxide (NO) delivery nanoplatform for targeting the MDR tumors based on core-shell structured nanocomposites. The mesoporous silica shell provided abundant sites for modification of the NO donor, N-diazeniumdiolate, and tumor-targeting molecule, folic acid (FA), and enabled high encapsulation capacity for doxorubicin (DOX) loading. Under NIR light irradiation, the generation of NO gas can efficiently augment chemotherapeutic effects via the inhibition of P-gp expression. Simultaneously, the photothermal conversion agents of the Cu2-xSe core produce a large amount of heat for photothermal therapy (PTT). Finally, this combinational gas/chemo/PTT not only displays a superior and synergistic effect for overcoming MDR cancer, but also provides an efficient strategy to construct a multifunctional nano-drug delivery system with diversified therapeutic modalities.

Prostate-specific membrane antigen (PSMA) is highly expressed on the surface of most prostate tumor cells and is considered a promising target for prostate cancer imaging and treatment. It is possible to establish a PSMA-targeted theranostic probe to achieve early diagnosis and treatment of this cancer type. In this contribution, we prepared a multifunctional melanin-like polydopamine (PDA) nanocarrier decorated with a small-molecule PSMA inhibitor, N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-(S)-l-lysine (DCL). PDA-DCL was then functionalized with perfluoropentane (PFP) and loaded with the photosensitizer chlorin e6 (Ce6) to give Ce6@PDA-DCL-PFP, which was successfully used for ultrasound-guided combined photodynamic/photothermal therapy (PDT/PTT) of prostate cancer. Compared with the corresponding non-targeted probe (Ce6@PDA-PEG-PFP), our targeted probe induced higher cellular uptake in vitro (6.5-fold) and more tumor accumulation in vivo (4.6-fold), suggesting strong active targeting capacity. Meanwhile, this new nanoplatform significantly enhanced the ultrasound contrast signal at the tumor site in vivo, thus facilitating precise and real-time detection of the tumor. In addition, this Ce6-loaded PDA nanoplatform produced a synergistic effect of PDT and PTT under 660 nm and 808 nm irradiation, inducing a more efficient killing effect compared with the individual therapy in vitro and in vivo. Furthermore, the tumor in the targeted group was more effectively suppressed than that in the non-targeted group under the same irradiation condition. This multifunctional probe may hold great potential for precise and early theranostics of prostate cancer.

Developing injectable hydrogels with near-infrared (NIR)-responsive photothermal effects has increasingly become a promising strategy for local cancer treatment via combinational photothermal-chemotherapy. Herein, a biocompatible hydrogel with a remarkable shear-thinning and recovery capability for injection application was fabricated from 4-arm-PEG-SH and tannic acid through chemical crosslinking and multiple physical interactions. Benefiting from the formation of dynamic TA/Fe3+ complexes within gel networks, the obtained hydrogel exhibited an intrinsic NIR absorption property for photothermal ablation of tumor cells, and enhanced cellular uptake of chemotherapeutic drugs. Both in vitro and in vivo experiments revealed that the injectable hydrogel exhibited an excellent biocompatibility and a synergistic therapeutic effect on tumor growth via combinational photothermal-chemotherapy. Therefore, this work provides a promising attempt to develop an injectable and NIR-responsive hydrogel from TA/Fe3+ complexes, which could work as a localized drug delivery platform for synergistic photothermal-chemotherapy.

Carbon monoxide (CO) can cause mitochondrial dysfunction, inducing apoptosis of cancer cells, which sheds light on a potential alternative for cancer treatment. However, the existing CO-based compounds are inherently limited by their chemical nature, such as high biological toxicity and uncontrolled CO release. Therefore, a nanoplatform - UmPF - that addresses such pain points is urgently in demand. In this study, we have proposed a nanoplatform irradiated by near-infrared (NIR) light to release CO. Iron pentacarbonyl (Fe(CO)5) was loaded in the mesoporous polydopamine layer that was coated on rare-earth upconverting nanoparticles (UCNPs). The absorption wavelength of Fe(CO)5 overlaps with the emission bands of the UCNPs in the UV-visible light range, and therefore the emissions from the UCNPs can be used to incite Fe(CO)5 to control the release of CO. Besides, the catechol groups, which are abundant in the polydopamine structure, serve as an ideal locating spot to chelate with Fe(CO)5; in the meantime, the mesoporous structure of the polydopamine layer improves the loading efficiency of Fe(CO)5 and reduces its biological toxicity. The photothermal effect (PTT) of the polydopamine layer is highly controllable by adjusting the external laser intensity, irradiation time and the thickness of the polydopamine layer. The results illustrate that the combination of CO gas therapy (GT) and polydopamine PTT brought by the final nanoplatform can be synergistic in killing cancer cells in vitro. More importantly, the possible toxic side effects can be effectively prevented from affecting the organism, since CO will not be released in this system without near-infrared light radiation.

Dietary restriction (DR), as a natural intervention, not only benefits the neuroendocrine system, but also has an antiaging action. Acetylcholinesterase (AChE) is one of the most important bioactive substances and plays a major part in choline changes in the aging process. Thus, we aim to evaluate the effect of DR on AChE in the brains of aging animals. In this study, we synthesize a NIR fluorescent probe BD-AChE for the real-time and in situ monitoring of AChE level changes in living cells and living mice, notably in brains. In situ visualization with BD-AChE verified a decrease in the AchE level in the brains of mice aging models. Evidently, the prepared probe has the excellent capability of measuring AChE variation in the brains of aging mice with DR via NIR fluorescence bioimaging, indicating that long-term DR can effectively affect AChE levels in the brain. The attenuation of AChE level in the brain of aging mice after DR could be helpful in infering the advantageous impact of DR on age-related neurodegenerative disease, as a better treatment alternative in the future.

BODIPY dyes have recently been used for photothermal and photodynamic therapy of tumors. However, complex multi-material systems, multiple excitation wavelengths and the unclear relationship between BODIPY structures and their PTT/PDT efficiency are still major issues. In our study, nine novel BODIPY near-infrared dyes were designed and successfully synthesized and then, the relationships between BODIPY structures and their PTT/PDT efficiency were investigated in detail. The results showed that modifications at position 3,5 of the BODIPY core with conjugated structures have better effects on photothermal and photodynamic efficiency than the modifications at position 2,6 with halogen atoms. Density functional theory (DFT) calculations showed that this is mainly due to the extension of the conjugated chain and the photoinduced electron transfer (PET) effect. By encapsulating BDPX-M with amphiphilic DSPE-PEG2000-RGD and lecithin, the obtained NPs not only show good water solubility and biological stability, but also could act as superior agents for photothermal and photodynamic synergistic therapy of tumors. Finally, we obtained BODIPY NPs that exhibited excellent photothermal and photodynamic effects at the same time under single irradiation with an 808 nm laser (photothermal conversion efficiency: 42.76%, A/A0: ∼0.05). In conclusion, this work provides a direction to design and construct phototherapeutic nanoparticles based on BODIPY dyes for tumor treatment.

Near-infrared fluorophores are emerging as promising molecular tools for cancer theranostics because of their inherent biodegradability, low toxicity, and synthetic flexibility. However, they still suffer from several limitations, such as poor photostability and insufficient organelle-targeting stability during photothermal therapy. In this work, we introduce an "aldehyde functionalization" strategy for simultaneously enhancing photostability and mitochondria-immobilization of near-infrared fluorophores for the first time. Based on the proposed strategy, representative near-infrared organic molecules, namely AF-Cy, were rationally designed and synthesized. Upon aldehyde modification, the AF-Cy dyes displayed both remarkable photostability and mitochondrial-targeting stability. The strong absorption in the near-infrared region confers the AF-Cy dyes with outstanding fluorescent/photoacoustic imaging and photothermal therapy capabilities. Finally, in vitro and in vivo studies revealed the enhanced performance in inhibiting the growth of breast tumors under NIR laser radiation, and these results suggested the strong potential of AF-Cy dyes as efficient multimodal imaging-guided photothermal therapy agents, further highlighting the value of this simple strategy in the design high performance near-infrared fluorophores for tumor theranostics.

Second near-infrared window (NIR-II, 1000-1700 nm) absorption and fluorescent agents have attracted great attention because they can overcome the penetration limitation of the first near-infrared window (NIR-I, 750-1000 nm). However, these always "on" agents face the severe problem of being susceptible to retention and phagocytosis by the reticuloendothelial system after intravenous administration, which results in signal interference during diagnosis and side effects during treatment. Accordingly, tumor microenvironment-responsive smart agents (smart NIR-II agents), whose imaging and therapeutic functions can only be triggered in tumors, can overcome this limitation. Thus, NIR-II smart agents, which exhibit a combined response to the tumor microenvironment and NIR-II, make full use of the advantages of both triggers and improve the precision diagnosis and effective treatment of cancer. This review summarizes the recent advances in tumor microenvironment-activated NIR-II agents for tumor diagnosis and treatment, including smart NIR-II fluorescence imaging, photoacoustic imaging, photothermal therapy and photodynamic therapy. Finally, the challenges and perspectives of NIR-II smart agents for tumor diagnosis and treatment are proposed.

Development of bioresponsive theranostic nanoparticles to enhance cancer diagnostics and control cancer metastasis is highly desirable. In this study, we developed such a bioresponsive theranostic nanoparticle for synergistic photoimmunotherapy. In particular, these nanoparticles were constructed by embedding indocyanine green (ICG) into Mn2+-doped amorphous calcium carbonate (ACC(Mn)) nanoparticles, followed by loading of the Toll-like-receptor-7 agonist imiquimod (IMQ). The IMQ@ACC(Mn)-ICG/PEG nanoparticles respond to the acidic pH of the tumor microenvironment (TME) and co-deliver ICG and IMQ into the tumor. Selective phototherapy was achieved upon activation using a near-infrared laser. In the presence of IMQ and arising from phototherapeutically treated tumor cells, tumor-associated antigens give rise to a strong antitumor immune response. Reversal of the immunosuppressive TME via H+ scavenging of the tumor through ACC nanoparticles effectively inhibits tumor metastases. Moreover, the combination of ICG and Mn2+ also serves as an advanced contrast agent for cancer multimode imaging. Overall, these bioresponsive nanoparticles provide a promising approach for cancer theranostics with promising potential for future clinical translation.

International audience; Nanoemulsions (NEs) are biocompatible and stealth nanodroplets that can efficiently encapsulate hydrophobic cytoactive drugs in their oily core. NEs were shown to accumulate in tumors by enhanced permeability and retention (EPR) effect and thus display appealing features as nanocarriers to selectively deliver drugs to the tumors. However, to ensure efficient encapsulation with minimal early release, drugs must possess a high degree of lipophilicity. To circumvent this limitation, the latter could be transformed into prodrugs with enhanced hydrophobicity. In return, once delivered in the cell, the prodrug must be efficiently transformed into its active drug form. Herein we chemically and reversibly modified a near infrared Huda dye (HD) into pro-fluorophore (Pro-HD), a non-fluorescent and lipophilic prodrug model that was efficiently loaded in NEs. Thanks to the fluorogenecity of the system (fluorescence enhancement of 35-fold at 723 nm), we demonstrated that Pro-HD did not leak out of NEs, was efficiently delivered into cancer cells and was transformed in cellulo into HD. This proof of concept demonstrates the high potential of lipophilic "pro-fluorophore" approach for visualizing delivery of cargos using NEs as nanocarriers.