Minimizing the Heat Effect of Photodynamic Therapy Based on Inorganic Nanocomposites Mediated by 808 nm Near‐Infrared Light

Photodynamic therapy (PDT) based on photosensitizers (PSs) constructed with nanomaterials has become popular in cancer treatment, especially oral carcinoma cell. This therapy is characterized by improved PS accumulation in tumor regions and generation of reactive oxygen species (ROS) for PDT under specific excitation. In the selection of near‐infrared (NIR) window, 808 nm NIR light because it can avoid the absorption of water is particularly suitable for the application in PDT. Hence, multiband emissions under a single 808 nm near‐infrared excitation of Nd³⁺‐sensitized upconversion nanoparticles (808 nm UCNPs) have been applied for the PDT effect. 808 nm UCNPs serve as light converter to emit UV light to excite inorganic PS, graphitic carbon nitride quantum dots (CNQDs), thereby generating ROS. In this study, a nanocomposite consisting UCNPs conjugated with poly‐l ‐lysine (PLL) to improve binding with CNQDs is fabricated. According to the research results, NIR‐triggered nanocomposites of 808 nm UCNP‐PLL@CNs have been verified by significant improvement in ROS generation. Consequently, 808 nm UCNP‐PLL@CNs exhibit high capability for ROS production and efficient PDT in vitro and in vivo. Moreover, the mechanism of PDT treatment by 808 nm UCNP‐PLL@CNs is evaluated using the cell apoptosis pathway.     

DNA‐Assembled Core‐Satellite Upconverting‐Metal–Organic Framework Nanoparticle Superstructures for Efficient Photodynamic Therapy

DNA‐mediated assembly of core–satellite structures composed of Zr(IV)‐based porphyrinic metal‐organic framework (MOF) and NaYF₄,Yb,Er upconverting nanoparticles (UCNPs) for photodynamic therapy (PDT) is reported. MOF NPs generate singlet oxygen (¹O₂) upon photoirradiation with visible light without the need for additional small molecule, diffusional photosensitizers such as porphyrins. Using DNA as a templating agent, well‐defined MOF–UCNP clusters are produced where UCNPs are spatially organized around a centrally located MOF NP. Under NIR irradiation, visible light emitted from the UCNPs is absorbed by the core MOF NP to produce ¹O₂ at significantly greater amounts than what can be produced from simply mixing UCNPs and MOF NPs. The MOF–UCNP core–satellite superstructures also induce strong cell cytotoxicity against cancer cells, which are further enhanced by attaching epidermal growth factor receptor targeting affibodies to the PDT clusters, highlighting their promise as theranostic photodynamic agents.     

NIR Biosensing of Neurotransmitters in Stem Cell‐Derived Neural Interface Using Advanced Core–Shell Upconversion Nanoparticles

Nondestructive neurotransmitter detection and real‐time monitoring of stem cell differentiation are both of great significance in the field of neurodegenerative disease and regenerative medicine. Although luminescent biosensing nanoprobes have been developed to address this need, they have intrinsic limitations such as autofluorescence, scattering, and phototoxicity. Upconversion nanoparticles (UCNPs) have gained increasing attention for various biomedical applications due to their high photostability, low auto‐fluorescent background, and deep tissue penetration; however, UCNPs also suffer from low emission intensities due to undesirable energy migration pathways. To address the aforementioned issue, a single‐crystal core–shell–shell “sandwich” structured UCNP is developed that is designed to minimize deleterious energy back‐transfer to yield bright visible emissions using low power density excitations. These UCNPs show a remarkable enhancement of luminescent output relative to conventional β‐NaYF4:Yb,Er codoped UCNPs and β‐NaYF4:Yb,Er@NaYF4:Yb “active shell” alike. Moreover, this advanced core–shell–shell UCNP is subsequently used to develop a highly sensitive biosensor for the ultrasensitive detection of dopamine released from stem cell‐derived dopaminergic‐neurons. Given the challenges of in situ detection of neurotransmitters, the developed NIR‐based biosensing of neurotransmitters in stem cell‐derived neural interfaces present a unique tool for investigating single‐cell mechanisms associated with dopamine, or other neurotransmitters, and their roles in neurological processes.     

Red‐Emitting Upconverting Nanoparticles for Photodynamic Therapy in Cancer Cells Under Near‐Infrared Excitation

Upconverting nanoparticles (UCNPs) have attracted considerable attention as potential photosensitizer carriers for photodynamic therapy (PDT) in deep tissues. In this work, a new and efficient NIR photosensitizing nanoplatform for PDT based on red‐emitting UCNPs is designed. The red emission band matches well with the efficient absorption bands of the widely used commercially available photosensitizers (Ps), benefiting the fluorescence resonance energy transfer (FRET) from UCNPs to the attached photosensitizers and thus efficiently activating them to generate cytotoxic singlet oxygen. Three commonly used photosensitizers, including chlorine e6 (Ce6), zinc phthalocyanine (ZnPc) and methylene blue (MB), are loaded onto the alpha‐cyclodextrin‐modified UCNPs to form Ps@UCNPs complexes that efficiently produce singlet oxygen to kill cancer cells under 980 nm near‐infrared excitation. Moreover, two different kinds of drugs are co‐loaded onto these nanoparticles: chemotherapy drug doxorubicin and PDT agent Ce6. The combinational therapy based on doxorubicin (DOX)‐induced chemotherapy and Ce6‐triggered PDT exhibits higher therapeutic efficacy relative to the individual means for cancer therapy in vitro.     

Dual‐Stimuli Responsive Nanotheranostics for Multimodal Imaging Guided Trimodal Synergistic Therapy

Multimodal imaging guided synergistic therapy promises more accurate diagnosis than any single imaging modality, and higher therapeutic efficiency than any single one or their simple “mechanical” combination. Herein, we report a dual‐stimuli responsive nanotheranostic based on a hierarchical nanoplatform, composed of mesoporous silica‐coated gold nanorods (GNR@SiO2), Indocyanine Green (ICG), and 5‐fluorouracil (5‐FU), for in vivo multimodal imaging guided synergistic therapy. The 5‐FU loaded ICG‐conjugated silica‐coated gold nanorods (GNR@SiO2‐5‐FU‐ICG) was able to response specifically to the two stimuli of pH change and near‐infrared (NIR) light irradiation. Both the NIR light irradiation and acidic environment accelerated the 5‐FU release. Meanwhile, the heat generation and singlet oxygen production can be induced by GNR@SiO2‐5‐FU‐ICG upon light irradiation. Most intriguingly, the nanoplatform also promises multimodal imaging such as two‐photon luminescence, fluorescence, photoacoustic, photothermal imaging, as well as trimodal synergistic therapy such as photothermal therapy (PTT), photodynamic therapy (PDT), and chemotherapy. The cancer theranostic capability of GNR@SiO2‐5‐FU‐ICG was evaluated both in vitro and in vivo. The trimodal synergistic therapy with the guidance of multimodal imaging exhibited remarkably enhanced treatment efficacy. This concept of a hierarchical nanoplatform integrates multiple diagnostic/therapeutic modalities into one platform, which can potentially be applied as personalized nanomedicine with drug delivery, diagnosis, and treatment.     

Aptamers and Their Applications in Nanomedicine

Aptamers are composed of short RNA or single‐stranded DNA sequences that, when folded into their unique 3D conformation, can bind to their targets with high specificity and affinity. Although functionally similar to protein antibodies, oligonucleotide aptamers offer several advantages over protein antibodies in biomedical and clinical applications. Through the enhanced permeability and retention effect, nanomedicines can improve the therapeutic index of a treatment and reduce side effects by enhancing accumulation at the disease site. However, this targets tumors passively and, thus, may not be ideal for targeted therapy. To construct ligand‐directed “active targeting” nanobased delivery systems, aptamer‐equipped nanomedicines have been tested for in vitro diagnosis, in vivo imaging, targeted cancer therapy, theranostic approaches, sub‐cellular molecule detection, food safety, and environmental monitoring. This review focuses on the development of aptamer‐conjugated nanomedicines and their application for in vivo imaging, targeted therapy, and theranostics.     

A Novel Theranostic Nanoprobe for In Vivo Singlet Oxygen Detection and Real‐Time Dose–Effect Relationship Monitoring in Photodynamic Therapy

Singlet oxygen, as the main member of reactive oxygen species, plays a significant role in cancer photodynamic therapy. However, the in vivo real‐time detection of singlet oxygen remains challenging. In this work, a Förster resonance energy transfer (FRET)‐based upconversion nanoplatform for monitoring the singlet oxygen in living systems is developed, with the ability to evaluate the in vivo dose–effect relationship between singlet oxygen and photodynamic therapy (PDT) efficacy. In details, this nanoplatform is composed of core–shell upconversion nanoparticles (UCNPs), photosensitizer MC540, NIR dye IR‐820, and poly(acryl amine) PAA‐octylamine, where the UCNPs serve as an energy donor while IR‐820 serves as an energy acceptor. The nanoparticles are found to sensitively reflect the singlet oxygen levels generated in the tumor tissues during PDT, by luminescence intensity changes of UNCPs at 800 nm emission. Furthermore, it could also enable tumor treatment with satisfactory biocompatibility. To the best knowledge, this is the first report of a theranostic nanoplatform with the ability to formulate the in vivo dose–effect relationship between singlet oxygen and PDT efficacy and to achieve tumor treatment at the same time. This work might also provide an executable strategy to evaluate photodynamic therapeutic efficacy based on singlet oxygen pathway.     

NIR Photoresponsive Crosslinked Upconverting Nanocarriers Toward Selective Intracellular Drug Release

An NIR‐responsive mesoporous silica coated upconverting nanoparticle (UCNP) conjugate is developed for controllable drug delivery and fluorescence imaging in living cells. In this work, antitumor drug doxorubicin (Dox) molecules are encapsulated within cross‐linked photocaged mesoporous silica coated UCNPs. Upon 980 nm light irradiation, Dox could be selectively released through the photocleavage of theo‐nitrobenzyl (NB) caged linker by the converted UV emission from UCNPs. This NIR light‐responsive nanoparticle conjugate demonstrates high efficiency for the controlled release of the drug in cancer cells. Upon functionalization of the nanocarrier with folic acid (FA), this photocaged FA‐conjugated silica‐UCNP nanocarrier will also allow targeted intracellular drug delivery and selective fluorescence imaging towards the cell lines with high level expression of folate receptor (FR).     

Integration of IR‐808 Sensitized Upconversion Nanostructure and MoS2 Nanosheet for 808 nm NIR Light Triggered Phototherapy and Bioimaging

Near infrared (NIR) light triggered phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT) affords superior outcome in cancer treatment. However, the reactive oxygen species (ROS) generated by NIR‐excited upconversion nanostructure is limited by the feeble upconverted light which cannot activate PDT agents efficiently. Here, an IR‐808 dye sensitized upconversion nanoparticle (UCNP) with a chlorin e6 (Ce6)‐functionalized silica layer is developed for PDT agent. The two booster effectors (dye‐sensitization and core–shell enhancement) synergistically amplify the upconversion efficiency, therefore achieving superbright visible emission under low 808 nm light excitation. The markedly amplified red light subsequently triggers the photosensitizer (Ce6) to produce large amount of ROS for efficient PDT. After the silica is endowed with positive surface, these PDT nanoparticles can be easily grafted on MoS₂ nanosheet. As the optimal laser wavelength of UCNPs is consistent with that of MoS₂ nanosheet for PTT, the invented nanoplatform generates both abundant ROS and local hyperthermia upon a single 808 nm laser irradiation. Both the in vitro and in vivo assays validate that the innovated nanostructure presents excellent cancer cell inhibition effectiveness by taking advantages of the synergistic PTT and PDT, simultaneously, posing trimodal (upconversion luminescence/computed tomography (CT)/magnetic resonance imaging (MRI) imaging capability.     

Engineering of Lanthanide‐Doped Upconversion Nanoparticles for Optical Encoding

Lanthanide‐doped upconversion nanoparticles (UCNPs) are an emerging class of luminescent materials that emit UV or visible light under near infra‐red (NIR) excitations, thereby possessing a large anti‐Stokes shift property. Due to their sharp excitation and emission bands, excellent photo‐ and chemical stability, low autofluorescence, and high tissue penetration depth of the NIR light used for excitation, UCNPs have surpassed conventional fluorophores in many bioapplications. A better understanding of the mechanism of upconversion, as well as the development of better approaches to preparing UCNPs, have provided more opportunities to explore their use for optical encoding, which has the potential for applications in multiplex detection and imaging. With the current ability to precisely control the microstructure and properties of UCNPs to produce particles of tunable emission, excitation, luminescence lifetime, and size, various strategies for optical encoding based on UCNPs can now be developed. These optical properties of UCNPs (such as emission and excitation wavelengths, ratiometric intensity, luminescence lifetime, and multicolor patterns), and the strategies employed to engineer these properties for optical encoding of UCNPs through homogeneous ion doping, heterogeneous structure fabrication and microbead encapsulation are reviewed. The challenges and potential solutions faced by UCNP optical encoding are also discussed.     

Recent Advances in Upconversion Nanoparticles‐Based Multifunctional Nanocomposites for Combined Cancer Therapy

Lanthanide‐doped upconversion nanoparticles (UCNPs) have the ability to generate ultraviolet or visible emissions under continuous‐wave near‐infrared (NIR) excitation. Utilizing this special luminescence property, UCNPs are approved as a new generation of contrast agents in optical imaging with deep tissue‐penetration ability and high signal‐to‐noise ratio. The integration of UCNPs with other functional moieties can endow them with highly enriched functionalities for imaging‐guided cancer therapy, which makes composites based on UCNPs emerge as a new class of theranostic agents in biomedicine. Here, recent progress in combined cancer therapy using functional nanocomposites based on UCNPs is reviewed. Combined therapy referring to the co‐delivery of two or more therapeutic agents or a combination of different treatments is becoming more popular in clinical treatment of cancer because it generates synergistic anti‐cancer effects, reduces individual drug‐related toxicity and suppresses multi‐drug resistance through different mechanisms of action. Here, the recent advances of combined therapy contributed by UCNPs‐based nanocomposites on two main branches are reviewed: i) photodynamic therapy and ii) chemotherapy, which are the two most widely adopted therapies of UCNPs‐based composites. The future prospects and challenges in this emerging field will be also discussed.     

Flexible Cationic Nanoparticles with Photosensitizer Cores for Multifunctional Biomedical Applications

One challenge for multimodal therapy is to develop appropriate multifunctional agents to meet the requirements of potential applications. Photodynamic therapy (PDT) is proven to be an effective way to treat cancers. Diverse polycations, such as ethylenediamine‐functionalized poly(glycidyl methacrylate) (PGED) with plentiful primary amines, secondary amines, and hydroxyl groups, demonstrate good gene transfection performances. Herein, a series of multifunctional cationic nanoparticles (PRP) consisting of photosensitizer cores and PGED shells are readily developed through simple dopamine‐involving processes for versatile bioapplications. A series of experiments demonstrates that PRP nanoparticles are able to effectively mediate gene delivery in different cell lines. PRP nanoparticles are further validated to possess remarkable capability of combined PDT and gene therapy for complementary tumor treatment. In addition, because of their high dispersities in biological matrix, the PRP nanoparticles can also be used for in vitro and in vivo imaging with minimal aggregation‐caused quenching. Therefore, such flexible nanoplatforms with photosensitizer cores and polycationic shells are very promising for multimodal tumor therapy with high efficacy.     

Pulsed laser reshaping and fragmentation of upconversion nanoparticles — from hexagonal prisms to 1D nanorods through “Medusa”-like structures

One dimensional (1D) nanostructures attract considerable attention, enabling a broad application owing to their unique properties. However, the precise mechanism of 1D morphology attainment remains a matter of debate. In this study, ultrafast picosecond (ps) laser-induced treatment on upconversion nanoparticles (UCNPs) is offered as a tool for 1D-nanostructures formation. Fragmentation, reshaping through recrystallization process and bioadaptation of initially hydrophobic (β-Na_1.5Y_1.5F₆: Yb³⁺, Tm³⁺/β-Na_1.5Y_1.5F₆) core/shell nanoparticles by means of one-step laser treatment in water are demonstrated. “True” 1D nanostructures through “Medusa”-like structures can be obtained, maintaining anti-Stokes luminescence functionalities. A matter of the one-dimensional UCNPs based on direction of energy migration processes is debated. The proposed laser treatment approach is suitable for fast UCNP surface modification and nano-to-nano transformation, that open unique opportunities to expand UCNP applications in industry and biomedicine.

     

Theranostic Upconversion Nanobeacons for Tumor mRNA Ratiometric Fluorescence Detection and Imaging‐Monitored Drug Delivery

Remote optical detection and imaging of specific tumor‐related biomarkers and simultaneous activation of therapy according to the expression level of the biomarkers in tumor site with theranostic probes should be an effective modality for treatment of cancers. Herein, an upconversion nanobeacon (UCNPs‐MB/Dox) is proposed as a new theranostic nanoprobe to ratiometrically detect and visualize the thymidine kinase 1 (TK1) mRNA that can simultaneously trigger the Dox release to activate the chemotherapy accordingly. UCNPs‐MB/Dox is constructed with the conjugation of a TK1 mRNA‐specific molecular beacon (MB) bearing a quencher (BHQ‐1) and an alkene handle modified upconversion nanoparticle (UCNP) through click reaction and subsequently loading with a chemotherapy drug (Dox). With this nanobeacon, quantitative ratiometric upconversion detection of the target with high sensitivity and selectivity as well as the target triggered Dox release in vitro is demonstrated. The sensitive and selective ratiometric detection and imaging of TK1 mRNA under the irradiation of near infrared light (980 nm) and the mRNA‐dependent release of Dox for chemotherapy in the tumor MCF‐7 cells and A549 cells are also shown. This work provides a smart and robust platform for gene‐related tumor theranostics.     

Photosensitive Nanoparticles Combining Vascular‐Independent Intratumor Distribution and On‐Demand Oxygen‐Depot Delivery for Enhanced Cancer Photodynamic Therapy

In drug delivery, the poor tumor perfusion results in disappointing therapeutic efficacy. Nanomedicines for photodynamic therapy (PDT) greatly need deep tumor penetration due to short lifespan and weak diffusion of the cytotoxic reactive oxygen species (ROS). The damage of only shallow cells can easily cause invasiveness and metastasis. Moreover, even if the nanomedicines enter into deeper lesion, the effectiveness of PDT is limited due to the hypoxic microenvironment. Here, a deep penetrating and oxygen self‐sufficient PDT nanoparticle is developed for balanced ROS distribution within tumor and efficient cancer therapy. The designed nanoparticles (CNPs/IP) are doubly emulsified (W/O/W) from poly(ethylene glycol)‐poly(ε‐caprolactone) copolymers doped with photosensitizer IR780 in the O layer and oxygen depot perfluorooctyl bromide (PFOB) inside the core, and functionalized with the tumor penetrating peptide Cys‐Arg‐Gly‐Asp‐Lys (CRGDK). The CRGDK modification significantly improves penetration depth of CNPs/IP and makes the CNPs/IP arrive at both the periphery and hypoxic interior of tumors where the PFOB releases oxygen, effectively alleviating hypoxia and guaranteeing efficient PDT performance. The improved intratumoral distribution of photosensitizer and adequate oxygen supply augment the sensitivity of tumor cells to PDT and significantly improve PDT efficiency. Such a nanosystem provides a potential platform for improved therapeutic index in anticancer therapy.     

Binary Nanoparticle Superlattices for Plasmonically Modulating Upconversion Luminescence

Engineering a facile and controllable approach to modulate the spectral properties of lanthanide‐doped upconversion nanoparticles (UCNPs) is always an ongoing challenge. Herein, long‐range ordered, distinct two‐dimensional (2D) binary nanoparticle superlattices (BNSLs) composed of NaREF₄:Yb/Er (RE = Y and Gd) UCNPs and plasmonic metallic nanoparticles (Au NPs), including AB, AB₃, and AB₁₃ lattices, are fabricated via a slow evaporation‐driven self‐assembly to achieve plasmonic modulation of upconversion luminescence (UCL). Optical measurements reveal that typical red–green UCL from UCNPs can be effectively modulated into reddish output in BNSLs, with a drastically shortened lifetime. Notably, for AB₃‐ and AB₁₃‐type BNSLs with more proximal Au NPs around each UCNP, modified UCL with fine‐structured spectral lineshape is observed. These differences could be interpreted by the interplay of collective plasmon resonance introduced by 2D periodic Au arrays and spectrally selective energy transfer between UCNPs and Au. Thus, fabricating UCNP‐Au BNSLs with desired lattice parameters and NP configurations could be a promising way to tailor the UCL through controlled plasmonic modulation.     

Glutathione Mediated Size‐Tunable UCNPs‐Pt(IV)‐ZnFe2O4 Nanocomposite for Multiple Bioimaging Guided Synergetic Therapy

Here a multifunctional nanoplatform (upconversion nanoparticles (UCNPs)‐platinum(IV) (Pt(IV))?ZnFe₂O₄, denoted as UCPZ) is designed for collaborative cancer treatment, including photodynamic therapy (PDT), chemotherapy, and Fenton reaction. In the system, the UCNPs triggered by near‐infrared light can convert low energy photons to high energy ones, which act as the UV–vis source to simultaneously mediate the PDT effect and Fenton's reaction of ZnFe₂O₄ nanoparticles. Meanwhile, the Pt(IV) prodrugs can be reduced to high virulent Pt(II) by glutathione in the cancer cells, which can bond to DNA and inhibit the copy of DNA. The synergistic therapeutic effect is verified in vitro and in vivo results. The cleavage of Pt(IV) from UCNPs during the reduction process can shift the larger UCPZ nanoparticles (NPs) to the smaller ones, which promotes the enhanced permeability and retention (EPR) and deep tumor penetration. In addition, due to the inherent upconversion luminescence (UCL) and the doped Yb³⁺ and Fe³⁺ in UCPZ, this system can serve as a multimodality bioimaging contrast agent, covering UCL, X‐ray computed tomography, magnetic resonance imaging, and photoacoustic. A smart all‐in‐one imaging‐guided diagnosis and treatment system is realized, which should have a potential value in the treatment of tumor.     

Energy‐Converting Nanomedicine

Serious side effects to surrounding normal tissues and unsatisfactory therapeutic efficacy hamper the further clinic applications of conventional cancer‐therapeutic strategies, such as chemotherapy and surgery. The fast development of nanotechnology provides unprecedented superiorities for cancer therapeutics. Externally activatable therapeutic modalities mediated by nanomaterials, relying on highly effective energy transformation to release therapeutic elements/effects (cytotoxic reactive oxygen species, thermal effect, photoelectric effect, Compton effect, cavitation effect, mechanical effect or chemotherapeutic drug) for cancer therapies, categorized and termed as “energy‐converting nanomedicine,” have arouse considerable concern due to their noninvasiveness, desirable tissue‐penetration depth, and accurate modulation of therapeutic dose. This review summarizes the recent advances in the engineering of intelligent functional nanotherapeutics for energy‐converting nanomedicine, including photo‐based, radiation‐based, ultrasound‐based, magnetic field‐based, microwave‐based, electric field‐based, and radiofrequency‐based nanomedicines, which are enabled by external stimuli (light, radiation, ultrasound, magnetic field, microwave, electric field, and radiofrequency). Furthermore, biosafety issues of energy‐converting nanomedicine related to future clinical translation are also addressed. Finally, the potential challenges and prospects of energy‐converting nanomedicine for future clinical translation are discussed.     

A Novel Top‐Down Synthesis of Ultrathin 2D Boron Nanosheets for Multimodal Imaging‐Guided Cancer Therapy

Single atom nonmetal 2D nanomaterials have shown considerable potential in cancer nanomedicines, owing to their intriguing properties and biocompatibility. Herein, ultrathin boron nanosheets (B NSs) are prepared through a novel top‐down approach by coupling thermal oxidation etching and liquid exfoliation technologies, with controlled nanoscale thickness. Based on the PEGylated B NSs, a new photonic drug delivery platform is developed, which exhibits multiple promising features for cancer therapy and imaging, including: i) efficient NIR‐light‐to‐heat conversion with a high photothermal conversion efficiency of 42.5%, ii) high drug‐loading capacity and triggered drug release by NIR light and moderate acidic pH, iii) strong accumulation at tumor sites, iv) multimodal imaging properties (photoacoustic, photothermal, and fluorescence imaging), and v) complete tumor ablation and excellent biocompatibility. As far as it is known, this is the first report on the top‐down fabrication of ultrathin 2D B NSs by the combined thermal oxidation etching and liquid exfoliation, as well as their application as a multimodal imaging‐guided drug delivery platform. The newly prepared B NSs are also expected to provide a robust and useful 2D nanoplatform for various biomedical applications.     

Graphene‐Based Smart Platforms for Combined Cancer Therapy

The extensive research of graphene and its derivatives in biomedical applications during the past few years has witnessed its significance in the field of nanomedicine. Starting from simple drug delivery systems, the application of graphene and its derivatives has been extended to a versatile platform of multiple therapeutic modalities, including photothermal therapy, photodynamic therapy, magnetic hyperthermia therapy, and sonodynamic therapy. In addition to monotherapy, graphene‐based materials are widely applied in combined therapies for enhanced anticancer activity and reduced side effects. In particular, graphene‐based materials are often designed and fabricated as “smart” platforms for stimuli‐responsive nanocarriers, whose therapeutic effects can be activated by the tumor microenvironment, such as acidic pH and elevated glutathione (termed as “endogenous stimuli”), or light, magnetic, or ultrasonic stimuli (termed as “exogenous stimuli”). Herein, the recent advances of smart graphene platforms for combined therapy applications are presented, starting with the principle for the design of graphene‐based smart platforms in combined therapy applications. Next, recent advances of combined therapies contributed by graphene‐based materials, including chemotherapy‐based, photothermal‐therapy‐based, and ultrasound‐therapy‐based synergistic therapy, are outlined. In addition, current challenges and future prospects regarding this promising field are discussed.