Introduction

Cancer, one of the most pressing threats to global public health, has seen continuous advances in therapeutic methods; yet, numerous challenges persist.1 Conventional treatments, such as surgery, radiotherapy, and chemotherapy, are widely used in clinical practice, but they are associated with limitations including non-specific damage to normal cells, drug resistance, and high rates of postoperative recurrence and metastasis.2–4 In recent years, immunotherapy and targeted therapy have significantly improved the prognosis of some patients. However, factors like tumor microenvironment (TME) heterogeneity, immunosuppressive states, and drug resistance still restrict their efficacy—leading to unsatisfactory 5-year survival rates for patients with metastatic cancer—and therapy-related toxic side effects severely impair patients’ quality of life.5,6 Against this backdrop, the integration of nanotechnology has offered new perspectives for cancer treatment. Particularly, carbon dots (CDs)—a class of emerging nanomaterials—have gradually become a research focus due to their unique physicochemical properties and multimodal therapeutic potential.7–10

CDs are carbon-based nanomaterials typically with a size of less than 10 nm, characterized by excellent photoluminescent properties, high chemical stability, good biocompatibility, and tunable surface functionalization capabilities. Since their accidental discovery during the purification of single-walled carbon nanotubes in 200411 and their formal naming by Sun et al in 2006,12 research on CDs has advanced rapidly. Based on differences in structure and composition, CDs can be mainly categorized into four types: Carbon Quantum Dots (CQDs): Dominated by sp2/sp3 hybridized carbon, with abundant oxygen-containing functional groups (eg, hydroxyl, carboxyl) on their surface.13,14 Graphene Quantum Dots (GQDs): Composed of single or few-layer graphene, with oxygen/nitrogen-containing groups at the edges.15,16 Carbon Nanodots (CNDs): Mainly consisting of sp3 hybridized carbon, featuring high carbonization degree but no obvious lattice structure.17 Carbonized Polymer Dots (CPDs): Comprising a carbon core and a polymer/carbon hybrid structure, with the surface modified by abundant functional groups or polymer chains.18 Early research on CDs focused primarily on environmental and energy fields. In recent years, however, their potential in biomedicine—especially in cancer therapy—has become increasingly prominent.7,19–21

CDs exhibit diverse application strategies in cancer therapy, mainly including targeted delivery and the implementation of multiple therapeutic modalities. For instance, through surface functional modification, CDs can specifically recognize tumor cell markers to achieve precise targeted delivery of drugs, thereby enhancing therapeutic efficacy and reducing damage to normal tissues.22,23 Additionally, CDs can be applied in various cancer therapeutic strategies such as photodynamic therapy (PDT), photothermal therapy (PTT), chemodynamic therapy (CDT), sonodynamic therapy (SDT), gas therapy (GT), immunotherapy, gene therapy, and nanozyme-based therapy.24–26Figure 1 illustrates the diverse strategies of carbon dots for cancer therapy. Given the significant research value and broad application prospects of carbon dots in the field of tumor therapy, this review will comprehensively and systematically summarize the application strategies of carbon dots in tumor therapy, thoroughly explore their targeting, delivery, anticancer mechanisms of action, as well as various therapeutic strategies. It aims to provide comprehensive and in-depth theoretical references for relevant researchers, and promote the further development and application of carbon dots in the field of tumor therapy.

Figure 1 A summary of various application strategies of carbon dots in cancer treatment.

Two Critical Applications of Carbon Dots in Cancer Therapy: Drug Delivery and Targeting

Carbon dots (CDs) hold significant implications for drug delivery and targeting in cancer therapy. Their unique physicochemical properties enable them to serve as drug carriers, and precise targeting of tumor cells can be achieved through surface modification. This not only enhances the drug concentration at tumor sites but also improves therapeutic efficacy. In recent years, the application of CDs in drug delivery systems (DDSs) has undergone continuous development, demonstrating promising prospects for clinical translation. The following section provides a detailed overview of the advances in CDs for drug delivery and targeting in cancer therapy.

Drug Delivery SystemsEfficient Drug Loading

In terms of drug loading efficiency, CDs achieve ultra-high drug loading rates approaching 90% via covalent conjugation or non-covalent interactions (eg, electrostatic interaction, π-π stacking) between their abundant surface functional groups (such as amino and carboxyl groups) and drug molecules. For instance, a covalent conjugation system composed of polyamine-modified CDs and doxorubicin (DOX) has achieved a drug loading capacity (DLC) of 62.8%.27 Meanwhile, manganese-nitrogen dual-doped carbon quantum dots (Mn,N-CQDs) loaded with methotrexate (MTX) through electrostatic interaction exhibit an even higher drug loading efficiency (DLE) of 91%, which is significantly superior to that of traditional nanocarriers.28 As illustrated in Figure 2a and b, Xie et al synthesized water-soluble large amino acid-mimetic glutathione carbon quantum dots (LAAM GSH-CQDs) via a rapid route using reduced glutathione (GSH) as the precursor. The chemotherapeutic drug DOX was loaded onto LAAM GSH-CQDs through π-π stacking interactions. This system demonstrates a remarkably higher DLC compared to commercial DOX liposomes.29 The mechanism underlying this efficient drug loading not only relies on the surface charge properties of CDs—evidenced by the reversal of ζ-potential from −24.6 mV to +20.57 mV30—but also benefits from their nanoscale size (<10 nm) and functionalizable surface. For example, core-shell structures (MIP@g-CQDs) constructed via molecularly imprinted polymer (MIP) technology significantly enhance the MTX-binding capacity severalfold through specific recognition cavities.31 Notably, doping strategies (eg, N/S co-doping) can further optimize drug loading performance. For instance, N/S co-doping into CQDs markedly improves the loading rate of the AKT inhibitor Capivasertib.32

Figure 2 (a) A synthesis diagram of LAAM GSH-CQDs. (b) A schematic diagram showing the structure of LAAM GSH-CQDs. Reproduced with permission.29 (c) Cumulative MTX release from MIP@g-CQD and NIP@g-CQD at pH 7.4, 37°C & pH 5, 41°C and at pH 7.4, 41°C & pH 5, 37°C (Three replicates have been done). Reproduced with permission.31 (d) chemo-and photo-therapeutic actions of CNC/APTES/FA and CNC/APTES/FA/Cdots in Hela cells. (e and f) DOX-CNC/APTES/FA/Cdots at pH 5.6 and pH 7.4 (dotted line) without light radiation and (solid line) with light radiation. Reproduced with permission.33

Controlled Drug Release

In the aspect of controlled drug release, CD-based systems enable precise spatiotemporal regulation of drug release by responding to the characteristics of the tumor microenvironment (TME), such as acidic pH and high levels of reduced GSH. pH-responsive designs are particularly prominent: Mn,N-CQDs exhibit a drug release rate of 80% at pH 5.5,28 while the D-Biotin/DOX@mPEG-OAL/N-CQD system based on oxidized sodium alginate releases a much higher amount of drug (65.6%) under acidic conditions (pH 5.0) compared to physiological environments (pH 7.4).34 In addition, reduction-sensitive CDs (eg, LAAM GSH-CQDs) form hexameric hydration layers via hydrogen bonding, which triggers drug release in the presence of high GSH concentrations in tumors while maintaining long-term storage stability.29

Researchers have also developed a more complex cascade release system. For example, mesoporous silica composite carriers (DOX@N-CQD/HA-pSiO2) achieve dual pH-responsive release through the synergistic effect of hyaluronic acid (HA) gating and CDs.35 The advantage of these systems lies in the dynamic matching between drug release kinetics and the pathological microenvironment. As depicted in Figure 2c, the core-shell structured MIP@g-CQD designed by Nasiriani et al exhibits only minimal drug release in normal tissues (pH 7.4, 37°C), while the release rate increases by more than 3-fold in tumor tissues (pH 5, 41°C), thereby effectively avoiding systemic toxicity.31 It is worth emphasizing that the fluorescent properties of CDs have been innovatively integrated into the delivery process. For example, ultra-small aminated CDs allow real-time tracking of the nucleocytoplasmic separation of DOX in cells, providing a visualization tool for therapeutic monitoring.27

Multimodal Therapeutic Platforms

To address the challenge of crossing physiological barriers, tryptophan-derived CDs can penetrate the blood-brain barrier (BBB) via the LAT1 transporter, opening new avenues for the treatment of central nervous system (CNS) diseases.36 Additionally, mitochondrial-targeted delivery systems can improve the biodistribution of CQDs in organs, significantly prolonging the retention time of DOX in tumor tissues.37

Multifunctional integrated systems, such as starch@MOF(Mn-Zn) bionanocomposites, can simultaneously load DOX and 5-fluorouracil (5-FU). These composites achieve synergistic co-release of dual drugs through their porous structure (with a specific surface area of 275.98 m2/g), and their photoluminescent properties support the visualization of the therapeutic process.38 Furthermore, the photothermal and photodynamic properties of CDs have been extensively explored. As shown in Figure 2d–f, Thu Thi Anh et al developed a hybrid material by conjugating cellulose nanocrystals (CNCs) with folic acid, incorporating carbon quantum dots (Cdots), and loading DOX. This hybrid not only possesses fluorescent properties but also generates photosensitive singlet oxygen (1O2) and exhibits photothermal behavior. Furthermore, light irradiation can promote the release of DOX, endowing the system with reactive oxygen species (ROS)-mediated photodynamic activity.33

Targeting StrategiesSurface Modification

In terms of surface modification strategies, researchers have significantly improved targeting efficiency through functional molecule conjugation and exosome biomimetic coating technologies. For instance, the PFPNS@PDA@MS-PEI nanohybrid platform enhances tumor cell uptake by layer-by-layer assembly of polydopamine (PDA) and polyethyleneimine (PEI), leveraging the pH-responsive property of PEI.39 Additionally, Tiwari et al adopted an exosome encapsulation strategy (Ex-DC@CQDs and Ex@MTX-CQDs) to achieve active targeting via heparan sulfate proteoglycan (HSPG) receptors retained on the surface of breast cancer-derived exosomes. As illustrated in Figure 3a, observation of differential fluorescence intensity revealed a significant accumulation enhancement of EX-DC@CQDs in the cytoplasm. This phenomenon is primarily attributed to the HSPG proteins on their surface—acting as targeting motifs, these HSPG proteins can specifically bind to HSPG surface receptors, thereby facilitating the efficient enrichment of EX-DC@CQDs in the cytoplasm and endowing them with a significantly higher tumor accumulation efficiency compared to free drugs.40 Antibody/aptamer modification has also been integrated; for example, a HER2 aptamer-guided carbon dot system achieves 96.13% targeted release of docetaxel in HER2-positive breast cancer,41 while CDs/CS-FA (chitosan-folic acid-modified CDs) significantly improves HeLa cell uptake efficiency through folate receptor-mediated internalization.42

Figure 3 (a) Confocal based characteristic presence of HSPG protein following staining with syndican1 antibody (Catalog # MA5–32600) on Exo. Reproduced with permission.40 (b) In vitro release of DOX from CDs/CS-FA nanocarrier at 37°C in PBS buffer (pH 7.4 and 5.0). Reproduced with permission.42 (c) LbL scheme for the manufacturing of the functionalizing nanopar-ticles coated with a multilayered nanocoating consisting of seven layers, where the CH has been used as polycation (positive charged) while the CS as polyanion (negative charged). The CQDs are embedded in the core of the LbL-nanoparticles, while DOXO is incorporated within the CH layer and DTX within the CS layer. Reproduced with permission.43

Self-Targeting

In the context of self-targeting strategies, carbon dots (CDs) exhibit inherent tumor-selective accumulation and therapeutic efficacy without reliance on exogenous targeting ligands, which is attributed to their tunable physicochemical properties and intrinsic interactions with the tumor microenvironment (TME). For instance, poly-L-lysine-modified carbon dot assemblies (Plys-CDs) with a precisely tuned particle size of approximately 40 nm can enhance tumor accumulation via the enhanced permeability and retention (EPR) effect, while maintaining high photothermal conversion efficiency to achieve potent photothermal therapy.44 Similarly, the pH-responsive doxorubicin-loaded nanosystem (DOX-CDs@LCP) also accumulates preferentially in tumor tissues through the EPR effect, and triggers on-demand drug release in the acidic TME, thereby improving antitumor activity while minimizing systemic toxicity.45 In terms of organelle targeting, negatively charged CDs modified with positively charged amphiphilic nanostructures can efficiently penetrate cells and target mitochondria, highlighting the critical role of surface charge modulation in intracellular self-targeting.46 Collectively, these findings demonstrate that rational regulation of the particle size, surface charge, and microenvironment responsiveness of CDs enables the full exploitation of their intrinsic capabilities for tumor-selective accumulation and organelle localization. This provides a promising avenue for the construction of simplified yet highly efficient targeted nanotherapeutic platforms.

Tumor Microenvironment (TME) Responsiveness

In the in-depth development of TME-responsive strategies, researchers have focused on the tumor-specific acidic, redox, and enzymatic microenvironments to construct multi-level responsive intelligent delivery systems. For example, pH-sensitive materials (such as PEI and chitosan) are used to achieve specific drug release in the tumor interstitial fluid (pH 6.5). As illustrated in Figure 3b, chitosan-based CDs/CS-FA release 90% of doxorubicin within 30 hours at pH 5.0, whereas only 52% is released in normal tissues (pH 7.4).42 Further expansion to redox responsiveness has been explored: folate-targeted CQDs synthesized via plasma electrochemistry retain photosensitive groups to enable reactive oxygen species (ROS)-triggered photodynamic therapy.47 Innovatively, strategies integrating enzyme-responsive mechanisms have also been developed. Selenium-doped carbon dots (SeCDs) alleviate cisplatin-induced nephrotoxicity through the GPX4 enzymatic pathway without compromising the chemotherapeutic efficacy of cisplatin, making them applicable for clinical prevention of acute kidney injury in cancer patients receiving cisplatin chemotherapy.48 Additionally, CD-PEI consumes GSH via glutathione oxidase-like activity and reverses chemoresistance.49

Multifunctional Integrated Platforms

By deeply integrating surface modification and TME-responsive strategies, multifunctional integrated platforms have been constructed to achieve spatiotemporal precise regulation. For example, AMP-CDs@5-Fu realizes zero-order release kinetics through an intertwined filament structure, and combines fluorescent tracing functionality to simultaneously monitor drug distribution.50 Furthermore, Desmond et al employed layer-by-layer assembly technology to co-load DOX and docetaxel (DTX) into chitosan-chondroitin sulfate multilayer nanoparticles (Figure 3c). These nanoparticles have a size of approximately 150 nm, with an encapsulation efficiency of 48% for both drugs. Moreover, their spherical morphology and seven-layer structure enable controlled drug release.43 In addition, the cetirizine-PLA microsphere system enhances controlled release capability via PEG-modified carbon dots; its spherical morphology (150 nm) and uniform surface properties optimize pharmacokinetics.51 Through the coupling of surface targeting ligands (eg, antibodies, aptamers) and TME-responsive elements (eg, pH-sensitive polymers, ROS-triggered bonds), these systems have successfully developed an “dynamic response-feedback” intelligent mode.

Therapeutic Strategies of Carbon Dots in Cancer Therapy

As a new type of carbon-based nanomaterial, carbon dots (CDs) exhibit versatile therapeutic strategies in cancer therapy owing to their favorable biocompatibility, tunable and modifiable surface functional groups, excellent photothermal conversion and photosensitizing capabilities, as well as fluorescent properties. These strategies include photodynamic therapy (PDT), photothermal therapy (PTT), chemodynamic therapy (CDT), sonodynamic therapy (SDT), gas therapy, immunotherapy, and gene therapy. Table 1 summarizes the advantages and disadvantages of various strategies. Subsequent sections will elaborate on these therapeutic strategies in detail.

Table 1. Advantages and disadvantages of the eight core application strategies of carbon dots in cancer therapy

Photodynamic Therapy

Photodynamic therapy (PDT) is a precise anticancer technology based on the synergistic effect of three components: photosensitizer, light, and oxygen. Its mechanism involves activating photosensitizers accumulated at tumor sites using light of a specific wavelength to induce the generation of reactive oxygen species (ROS, eg, singlet oxygen), which selectively destroy cancer cells while minimizing damage to normal tissues.99,100 The introduction of CDs as novel nanophotosensitizers has revolutionized PDT from molecular design to clinical application. Compared with traditional photosensitizers, CDs, with their ultra-small size (<10 nm), tunable light absorption/emission properties, excellent biocompatibility, and multifunctional surface chemical modification capabilities, not only enhance tumor-killing efficiency through improved penetration and targeted accumulation but also integrate diagnostic imaging (eg, fluorescence/photoacoustic imaging) with therapeutic functions via surface engineering, enabling “theranostics integration”.52,53 Furthermore, CDs can extend their light response range to the near-infrared (NIR) region through structural design (eg, heteroatom doping or conjugate modification), thereby overcoming the therapeutic limitation of traditional PDT caused by insufficient penetration depth of visible light. Meanwhile, their inherent antioxidant scavenging ability reduces phototoxicity to normal tissues.101

Optimization of Photosensitizing Performance of CDs

The yield of singlet oxygen (1O2) can be improved through precursor selection and doping strategies. For example, nitrogen-doped CDs (N-CDs) synthesized using 1-aminoanthraquinone as a precursor achieve a 1O2 yield of 35% under 635 nm laser irradiation, significantly inducing cancer cell apoptosis.102 As shown in Figure 4a and b, Jiang et al synthesized bromine-doped carbon dots (Br-CDs) that can achieve deep tissue penetration and efficient antitumor effects in the near-infrared (NIR) region (>700 nm) by enhancing the synergistic effect of type I/II reactive oxygen species (ROS).103 Meanwhile, via solvothermal or microwave synthesis strategies, researchers have developed CDs with core-shell structures, upconversion fluorescence, or pH-responsive properties (eg, Arg-CDs, CPDs). Their light-controlled ROS release capability, combined with targeting functions (eg, folic acid modification, lysosomal localization), significantly improves the precision and safety of PDT.54–56

Figure 4 (a) A schematic diagram of the potential photoactivation process of ROS generation of BrCDs. (b) The UV-vis spectrum of BrCDs in DMF and PBS. Reproduced with permission.103 (c) Schematic illustration of MnZ@Au nanozyme-catalyzed cascade reaction for regulation of hypoxia and glucose metabolism. Upward arrows (↑) denote an increase, whereas downward arrows (↓) denote a decrease. (d) Schematic illustration of MnZ@Au mediated cascade reaction for PDT enhancement. Downward arrows (↓) denote a decrease. Reproduced with permission.104 (e) An illustration showing the performance mechanism of HF-SCDs@Cu. Tris(4,7-diphenyl-1,10-phenanthroline)ruthenium(II) chloride (RDPP), 1,3-diphenylisobenzofuran (DPBF), 3,3′,5,5′-tetramethylbenzidine (TMB), 5,5′-dithiobis-(2-nitrobenzoic acid) (DTNB), and singlet oxygen sensor green (SOSG). Upward arrows (↑) denote an increase, whereas downward arrows (↓) denote a decrease. (f) Illustration of PD-L1 downregulation caused by HF-SCDs@Cu. Reproduced with permission.105

Overcoming Tumor Microenvironment-Mediated Inhibition

To address TME characteristics such as hypoxia and high glucose metabolism, as illustrated in Figure 4c and d, Luo et al constructed a Mn-doped carbon dot (Mn-CD)-based hybrid system (MnZ@Au) by integrating zeolitic imidazolate framework-8 (ZIF-8) and gold nanoparticles. Through cascade glucose oxidase (GOx)- and catalase (CAT)-mimetic activities, this system simultaneously consumes glucose and generates oxygen in situ, thereby significantly enhancing the efficacy of PDT.104 Ruthenium-doped CDs (Ru-CDs) integrate triple modalities (photothermal/photodynamic/chemodynamic therapy) and, in combination with immune adjuvants, induce immunogenic cell death (ICD), establishing a new paradigm for CD-mediated synergistic therapy.106 In addition, composite systems of CDs with inorganic nanomaterials (eg, graphitic carbon nitride, metal-organic frameworks) or organic molecules (eg, porphyrins, BODIPY) expand the light response range (eg, activated by 980 nm NIR) through energy transfer or interface effects, while enabling theranostics integration.57,58,107 The advantage of these composite systems lies in their ability to compensate for the defects of single materials via inter-material synergy. However, how to regulate interface interactions to avoid energy loss remains a key challenge to be addressed.

Regulation of Cell Death Mechanisms and Remodeling of Immune Microenvironment

CDs can also regulate cell death mechanisms and the immune microenvironment during PDT. For instance, iron-doped CDs modified with chlorin e6 (Fe-CDs@Ce6) synergize with PDT by activating the ferroptosis pathway, and achieve therapeutic navigation via T2-weighted magnetic resonance imaging (MRI).108 As shown in Figure 4e and f, Bao et al utilized silkworm excrement-derived red fluorescent carbon dots (HF-SCDs@Cu), which degrade in the acidic TME to release ferrocene, Cu2⁺, and SCDs. This process triggers ferroptosis and PDT, degrades programmed death ligand 1 (PD-L1), and reverses hypoxia, thereby significantly enhancing the efficacy of immune checkpoint blockade therapy.105 Further studies have utilized the subcellular organelle targeting properties of CDs (eg, mitochondria, nucleoli) to amplify PDT effects by precisely disrupting organelle functions.59,109 This precise therapy at the subcellular organelle level enables efficient cell killing with lower ROS doses, reducing damage to normal cells. However, there is still a lack of clear understanding regarding the ROS diffusion range and mechanism of action of CDs in different subcellular organelles, and few studies have reported the quantitative relationship between subcellular organelle targeting efficiency and PDT efficacy.

Photothermal Therapy

Photothermal therapy (PTT) is a therapeutic technology that utilizes the conversion of light energy into thermal energy to treat diseases. It employs photothermal agents to convert absorbed light energy into heat, locally elevating the temperature of tumor tissues to induce cancer cell death.110 PTT based on CDs refers to a therapeutic approach that kills cancer cells by leveraging CDs to convert light energy into thermal energy under irradiation with light of a specific wavelength.111,112 The photothermal conversion mechanism involves the transition of electrons from the ground state to the excited state after CDs absorb light of a specific wavelength, followed by the return of electrons to the ground state via radiative and non-radiative pathways. The non-radiative relaxation process releases energy in the form of heat, generating a photothermal effect. Fluorescence quenching and aggregate molecular motion can enhance the non-radiative relaxation process, thereby improving the photothermal conversion efficiency.113

Regulation of Photothermal Properties of CDs

CDs significantly improve their photothermal conversion efficiency (PCE) through doping strategies (eg, doping with Fe, Cu, N) and structural engineering. For example, the PCE of Fe-doped CDs (M/Fe-CDs) is increased from 12.1% to 30.1%,60 while ultra-small self-assembled CDs (Arg-sCNDs) exhibit an ultra-high PCE of 77.09% under 730 nm laser irradiation.61 To enhance targeting ability and drug-controlled release performance, researchers have compounded CDs with liposomes, polymers (eg, polypyrrole), or metal nanomaterials (eg, gold nanorods) to construct multifunctional nanoplatforms. As shown in Figure 5a and b, Liu et al constructed a folic acid (FA)-targeted photothermal multifunctional nanoplatform by encapsulating carbon quantum dots (CQDs) and the anticancer drug doxorubicin (DOX) in liposomes. Meanwhile, indocyanine green (ICG), a near-infrared (NIR) photothermal agent, was embedded into the bilayer membrane to further enhance the photothermal effect and promote the rapid lysis of liposomes for drug release. Triggered by NIR laser irradiation, this engineered photothermal multifunctional nanoplatform not only exhibits excellent performance with a photothermal conversion efficiency as high as 47.14% but also achieves the controlled release of payloads.114 The hyaluronic acid-modified CQD-gold nanorod complex enables chemo-PTT synergistic therapy, significantly inhibiting tumor growth in mice.115 These studies verify the core advantage of CDs as photothermal agents: while maintaining low cytotoxicity (only 15% cytotoxicity at 14 mg/mL CQDs),62 they enhance PTT efficacy by regulating photothermal properties.

Figure 5 (a) Multi-modal synergistic antitumor therapy by CQDs/ICG/DOX@LPs-FA under near-infrared irradiation. (b) heating curves of the tumor region in 4 T1 tumor-bearing mice during 808nm laser irradiation. Reproduced with permission.114 (c) Viability of the CEMNDs-treated 4T1 cells at pH 7.4 with/without NIR-II irradiation. (d) Therapeutic efficacies of the CEMNDs under CDT, PTT, and combined therapy. (n=3,*p < 0.05). Reproduced with permission.64 (e and f) Fluorescence-guided photothermal ablation of a single A375 cell under irradiations (femtosecond laser, 800 nm, 5 s) with different powers. Reproduced with permission.116

Construction of CD-Based Multifunctional Nanoplatforms and Synergistic Therapy

Single PTT has limitations in addressing complex conditions such as tumor heterogeneity and distant metastasis. Therefore, researchers have compounded CDs with other functional materials to construct nanoplatforms with the capabilities of targeted delivery, drug-controlled release, and multimodal therapy. Through defect engineering (eg, polaron-induced lattice distortion) and heterostructure design (eg, Z-scheme BxC/C Janus quantum sheets), CDs are endowed with responsiveness to the near-infrared-II window, enabling deep tissue penetration (with a PCE of 60%).63,117 Meanwhile, Carbon dots are also endowed with immunomodulatory functions: for example, mannose-grafted Fe-CDs can deliver CpG-ODN to dendritic cells, promoting the expression of CD80/86;60 and aluminum-doped CD-crosslinked hydrogels (iCD@Gel) can synergize with damage-associated molecular patterns (DAMPs) to enhance antigen presentation after photothermal ablation.118 As shown in Figure 5c and d, Meng et al synthesized photoresponsive carbon-encapsulated magnetite nano-donuts (CEMNDs) with dual catalytic activity for photothermally enhanced chemodynamic therapy (CDT). Notably, CEMNDs can absorb light at 1064 nm: on one hand, they elevate the local temperature to achieve PTT; on the other hand, they increase iron ion release to enhance CDT efficacy. In in vivo experiments using a mouse model of invasive and drug-resistant metastatic triple-negative breast cancer, CEMNDs exhibited excellent synergistic antitumor effects without detectable significant systemic toxicity.64 Additionally, ruthenium-doped CDs (Ru-CDs) can achieve type I/II reactive oxygen species (ROS) generation, as well as photothermal and chemodynamic trimodal therapy, and induce a pan-cell death pathway.106

Precision and Clinical Translation Exploration of CD-Based PTT Systems

Guided by two-photon fluorescence imaging or MR/fluorescence dual-modal imaging, CDs enable a leap in therapeutic precision at the single-cell level: relying on the balanced two-photon absorption cross-section (7000 GM) and photoluminescence quantum yield (8.4%) of bifunctional N-doped CQDs, under irradiation with a 27.5 mW, 800 nm laser, they can complete the fluorescence-guided PTT process in just 5 seconds (Figure 5e and f), which is much faster than the control experiment without fluorescence guidance. In addition, aggregated CQDs can generate heat of sufficient intensity, and this heat is precisely confined to a very small area, thereby effectively limiting the range of action of heat treatment within cancer cells.116

At the same time, surface engineering strategies (eg, modification with folic acid or aptamer AS1411) can significantly improve tumor targeting efficiency: as constructed by Jiao et al, AS1411-Gd-CDs achieve efficient tumor inhibition under the guidance of magnetic resonance (MR)/fluorescence dual-modal imaging through aptamer-mediated active targeting.119 Furthermore, the exploration of novel CD precursors (eg, asphaltenes) and green synthesis methods (plant-derived CDs) promotes their progress toward low-cost, large-scale clinical applications.65,120 MoS2@CuS/FACDs nanoflowers combine CDs with ultrasound-responsive materials, enabling visual monitoring of the therapeutic process and dynamic evaluation of therapeutic efficacy.66

Chemodynamic Therapy

Chemodynamic therapy (CDT) is a cancer therapeutic strategy activated specifically by the tumor microenvironment (TME). Its core mechanism involves converting overexpressed hydrogen peroxide (H2O2) in tumor cells into highly toxic hydroxyl radicals (·OH) via Fenton or Fenton-like reactions, thereby inducing oxidative stress-mediated cell death.121 However, traditional CDT systems have significant limitations: on one hand, most metal-based catalysts (eg, Fe2⁺, Cu2⁺) suffer from low catalytic efficiency and are susceptible to reductive inactivation by GSH in the TME; on the other hand, free metal ions pose high metabolic risks in vivo and lack the ability for real-time monitoring of the therapeutic process. The emergence of CDs as novel carbon-based nanocatalytic materials provides a key solution to these bottlenecks. Their tunable electronic structure (achieved via heteroatom doping or surface modification) can enhance Fenton-like catalytic activity, while their high specific surface area and abundant functional groups facilitate the loading of catalytic components or targeting molecules. These properties collectively drive the development of CDT toward high efficiency, precision, and low toxicity.

CD-Metal Composite Systems

The development of composite systems of CDs and metal catalytic components has brought new breakthroughs in precise tumor theranostics. For example, PLGA@CQDs-CuPoxNPs encapsulates carbon quantum dots and copper peroxide nanoparticles (CuPoxNPs) within poly(lactic-co-glycolic acid) (PLGA). CDs enable real-time monitoring of nanoparticle accumulation in tumor tissues via fluorescence imaging (excitation wavelength: 400 nm), while CuPox triggers Fenton reactions in the acidic microenvironment (pH 5.5), achieving specific killing of tumor cells (killing rate > 85%) and protection of normal cells (killing rate ~10%).122 This fluorescence-guided CDT strategy penetrates deep into tumor tissues via a lysosomal escape mechanism, realizing a cancer treatment process where real-time monitoring and therapy proceed simultaneously. Notably, copper-based systems (eg, Cu-Sec-QDs, FA-CDs@Cu-x) exhibit unique advantages: copper quantum dots stabilized by selenocysteine directly catalyze Fenton reactions via Cu⁺, avoiding the rate-limiting step of Cu2⁺ reduction;67 folic acid-modified copper-doped super carbon dots not only enable targeted delivery but also exhibit near-infrared absorption (1000–1300 nm), endowing the system with a photothermal conversion efficiency of 54.3%. Local temperature elevation accelerates reactive oxygen species (ROS) generation, pioneering a new paradigm of photothermally enhanced CDT.68 For this “photothermal-chemodynamic” synergistic design, there remains a lack of quantitative studies on the specific impact of temperature elevation on the rate constant of Fenton-like reactions, and few studies have reported the variation law of ROS production across different temperature ranges. This direction may further optimize the synergy ratio between PTT and CDT.

Smart Responsive CD Systems: TME Regulation and Cascade Catalysis

To overcome the limitations of traditional CDT, smart responsive CD composites have been developed. To address the excessive consumption of ROS by GSH, Fe-CD nanosystems utilize the coordination between iron ions and CDs to quench fluorescence. When GSH triggers the reduction of Fe3⁺, it simultaneously restores fluorescence (for monitoring GSH depletion) and generates hydroxyl radicals, dynamically linking diagnosis and therapy.69 Cascade reaction systems, such as FeCD/GOx liposomes, catalyze the conversion of endogenous glucose to H2O2 via glucose oxidase (GOx), and in combination with ATP-responsive iron release, achieve H2O2 self-sufficient CDT under the guidance of magnetic resonance imaging.123 Notably, as shown in Figure 6a and b, He et al constructed a heterojunction-structured CD/TiSe2 composite, which in-situ generates multivalent components such as Ti3⁺ and Se0. In the acidic TME, this composite simultaneously achieves GSH depletion (mediated by Ti4⁺), Fenton catalysis (mediated by Ti3⁺), and immune activation (Se ions promote dendritic cell maturation). By organically integrating CDT with sonodynamic therapy and immunotherapy, it significantly enhances tumor killing efficiency.70 These innovative designs break the limitations of single therapies and form a synergistic enhancement model encompassing microenvironment responsiveness, cascade catalysis, and multimodal therapy.

Figure 6 (a) Schematic illustration of the in situ redox of CD/TiSe2 to excite chemodynamic activity. Upward arrows (↑) denote an increase, whereas downward arrows (↓) denote a decrease. (b) Schematic illustration of the in vitro anticancer therapy of CD/TiSe2 through in situ CDT-enhanced SDT and immunotherapy combined with αPD-L1 using bilateral tumor model. Reproduced with permission.70 (c) Fe ion release from IONCNs at different pH values with/without 980 nm irradiation. Reproduced with permission.71

Precision and Intelligence of CDT

Structural engineering of CDs enables precise and controllable therapeutic processes. Zhang et al synthesized manganese-doped mesoporous carbon nanoparticles (MnOx-MCN-NPs), which integrate chemotherapeutic drug loading (doxorubicin, DOX), a photothermal conversion efficiency of 44.2%, and pH/near-infrared (NIR) dual-responsive release capability. Upon NIR excitation, these nanoparticles synchronously enhance the Fenton reaction and drug release, exhibiting excellent synergistic anticancer efficiency both in vitro and in vivo.124 The FeOOH@PDA system modified with graphene quantum dots dynamically regulates magnetic resonance signals via MnO2 components, enabling real-time monitoring of the therapeutic process. Meanwhile, the photothermal effect of PDA increases CDT efficiency by 3-fold.125 Iron oxide-coated nitrogen-doped carbon nanosheets (IONCNs) represent a breakthrough advancement. As shown in Figure 6c, their 980 nm photothermal-triggered Fe2⁺/Fe3⁺ cycling not only maintains continuous Fenton reactions but also amplifies oxidative stress via the glutathione peroxidase-like activity of Fe3⁺. The cascade catalytic mechanism of photoregulated nanoenzymes has been verified in vivo.71 Currently, the application of this continuous catalytic mechanism based on metal ion valence cycling remains relatively rare in other CD-based CDT systems. How to further extend the catalytic cycle lifetime through the structural design of CDs is a crucial direction for future research.

Sonodynamic Therapy

Sonodynamic therapy (SDT) is an emerging non-invasive tumor therapeutic technology that activates sonosensitizers using low-intensity ultrasound to generate reactive oxygen species (ROS), thereby inducing tumor cell apoptosis.72 Compared with PDT, SDT leverages the deep penetration capability of ultrasound, enabling more effective treatment of deep-seated tumors. As a novel sonosensitizer, CDs exhibit a unique mechanism of action in SDT. Their surfaces are rich in oxygen-containing functional groups (eg, carboxyl, hydroxyl groups), which can efficiently absorb energy generated by cavitation bubbles under ultrasound activation to further produce ROS.121,126 Additionally, the narrow bandgap and long-lived excited state properties of CDs allow them to generate ROS efficiently even under low-intensity ultrasound. This SDT approach, combining ultrasound activation and CD properties, provides a new strategy for tumor therapy with high efficiency, low toxicity, and deep penetration capability.

Optimization Mechanisms and Structural Design of Sonosensitizing Performance of CDs

The ROS generation efficiency can be significantly improved through band engineering and heterostructure construction. For example, traditional inorganic sonosensitizers such as TiO2 have limited ROS yield due to their wide bandgap (3.2 eV). However, via narrow bandgap design (eg, MXene nanosheets with a bandgap of only 0.94 eV) and the construction of 0D/2D hybrid heterojunctions (HJs) between Ti3C2 nanosheets and graphitic nitrogen-doped CDs (Figure 7a and b), the carrier transport efficiency and ROS production efficiency are significantly enhanced, reaching 3.07 times that of commercial TiO2 nanoparticles.73 Wang et al constructed vanadium carbide-derived carbon dots (PMQDs). Owing to their efficient electron-hole pair migration/separation capability and narrow bandgap characteristic, PMQDs can serve as high-performance sonosensitizers to generate abundant reactive oxygen species (ROS) under ultrasound (US) irradiation, thereby significantly enhancing the efficacy of SDT.74 Meanwhile, semiconductor p-n junctions (eg, N-CD@TiO2-ₓ) adopt a Z-scheme carrier migration mechanism, increasing the generation rates of 1O2 and •OH by 4.3 and 4.5 times, respectively.127 Further studies have achieved the synergy between sonodynamic activity and multienzyme catalytic activity through a bimetal doping strategy (Fe-Ni-CDs). This not only amplifies ROS via POD/CAT cascade reactions but also catalyzes the dynamic balance of H2O2/O2 in the tumor microenvironment (TME), breaking through the oxygen-dependent bottleneck of SDT.75

Figure 7 (a) Schematic illustration of NIR-II photothermal and sonodynamic effects of CD@Ti3C2Tx heterojunctions. (b) The rate constant of DPBF decomposition in the presence of CD@Ti3C2Tx HJs or commercial TiO2 under US irradiation. Reproduced with permission.73 (c) Scheme of the decreased bandgap structures of Co9S8-x-X induced by VS-doping. (d) Comparison of the rate constant of 1O2 generated by Co9S8-x-1, Co9S8-x-2, Co9S8-x-3, and Co9S8-x-4. (e) Comparison of the chemodynamic activity of Co9S8, Co9S8-x-1, Co9S8-x-2, Co9S8-x-3, and Co9S8-x-4. Reproduced with permission.128

Targeting and Responsive Design of CDs: Key Pathways to Enhance SDT Precision

The design of CD targeting and biological responsiveness has become a key breakthrough to improve therapeutic precision. Through biomimetic modification (eg, cancer cell membrane encapsulation) or functional ligand (folic acid, RGD peptide) modification, the tumor accumulation efficiency of CDs is significantly enhanced. For instance, folic acid-modified N-GQDs (FA-N-GQDs) achieve a tumor cell labeling rate of over 96%.129 At the same time, researchers have developed intelligent responsive systems to synergize multiple therapeutic modalities: pH/GSH dual-responsive DOX@CDs@HPMAA nanocapsules enable combined sonodynamic-chemotherapy;76 the mitochondria/nucleus-targeted CDs-PpIX system improves SDT efficacy by 3 times through subcellular organelle localization.77 Notably, the inherent fluorescent properties of CDs have been further extended to near-infrared (NIR) imaging. For example, NIR phosphorescent CDs with a narrow bandgap (1.62 eV) and long-lived triplet state (11.4 μs) integrate deep tissue imaging (674–725 nm) and sonodynamic therapy functions, realizing the “theranostics integration” design concept.130

TME Regulation and Immune Synergy Mechanisms of CD-Based Composite Systems

Through heterojunction engineering (eg, CD@Ti3C2Tx MXene), CDs can not only enhance sonodynamic performance but also alleviate tumor hypoxia via photothermal conversion (with an efficiency of 64.5% in the NIR-II window), thereby enhancing deep tissue SDT efficacy and achieving complete tumor ablation.73 More cutting-edge research focuses on remodeling the immune microenvironment. As shown in Figure 7c–e, Cai et al prepared a series of defect-rich Co9S8-ₓ sonosensitizers with high sulfur vacancy (VS) levels by precisely regulating the weight ratio of sulfur and cobalt sources. During this process, the bandgap was significantly reduced from 2.06 eV to 1.54 eV, and the atomic ratio of Co2⁺ to Co3⁺ increased from 1.53 to 1.97. As a result, the defect-engineered biodegradable sulfide sonoenzymatic system exhibited remarkable enhanced effects in SDT, chemodynamic therapy (CDT), and antitumor immune responses. In the slightly acidic TME, the sonosensitizer could degrade slowly; the moderate reduction in its size not only facilitated enhanced tumor targeting ability and infiltration but also had a negligible impact on sonodynamic performance. Ultimately, the eradication of primary, distant, and metastatic tumors was achieved.128

Moreover, HABT-C nanoparticles possess triple enzyme-mimetic activities. They can act as self-cascading nanoenzymes to generate sufficient oxygen to alleviate hypoxia in the TME and produce abundant ROS. Simultaneously, they can effectively inhibit the expression of immunosuppressive mediators and promote the infiltration of immune effector cells into the TME, thereby reversing immune microenvironment suppression.131 These systems achieve synergistic inhibition of metastatic tumors through the combination of ROS-mediated immunogenic cell death (ICD) and checkpoint blockade therapy.

Gas Therapy

Gas therapy for cancer is an emerging tumor therapeutic strategy, whose core principle relies on leveraging the biological properties of specific gases (eg, nitric oxide, hydrogen, carbon dioxide) to interfere with the growth, proliferation, and metabolic processes of tumor cells.132 These gases can exert their effects through multiple mechanisms, such as regulating the intracellular redox state, influencing cell signaling pathways, inducing tumor cell apoptosis, or inhibiting tumor angiogenesis.78,79,133 However, traditional gas therapy faces two major bottlenecks: first, gas molecules are highly diffusible and have short half-lives, making it difficult to achieve precise accumulation at tumor sites; second, the lack of effective delivery carriers and controllable release mechanisms leads to low therapeutic efficiency and high risk of systemic side effects. As novel carbon-based nanomaterials, CDs offer new solutions to these issues, thanks to their excellent optical properties (eg, near-infrared fluorescence, photothermal conversion), good biocompatibility, and abundant surface functional groups.

CD-Mediated Targeted Gas Delivery and Controllable Release Mechanisms

The core value of CDs in gas therapy first lies in their ability to precisely regulate gas molecules: through surface modification or structural design, CDs can achieve efficient gas loading and tumor microenvironment (TME)-responsive release. Meanwhile, relying on their inherent properties, CDs address the “targeting-accumulation-release” challenges in gas delivery. For example, Liu et al synthesized L-arginine-derived carbon dots (Arg-dots), which efficiently catalyze endogenous hydrogen peroxide (H2O2) in tumors to generate nitric oxide (NO). The NO release amount is twice that of free L-arginine. Meanwhile, their ultrasmall size (2.5 nm) enables deep tumor penetration and renal clearance.134

Nitrated CDs (CD-NO) release NO under dual stimulation of glutathione (GSH) and photothermal effect. As shown in Figure 8a and b, the C-NO@PEG + NIR group exhibits significantly stronger intracellular green fluorescence compared to the CD@PEG + NIR group. This is mainly attributed to the reaction between NO and superoxide anion radicals (O2−) to form highly cytotoxic peroxynitrite ions (ONOO−). When additional GSH is added, the fluorescence intensity further increases—this is because more NO is supplemented, thereby promoting the generation of large amounts of ONOO− and achieving efficient tumor cell killing.80 Furthermore, gold-based porphyrin coordination polymers (Au-0-Por) promote the sustained release of carbon monoxide (CO) through cascade catalytic reactions, reversing the Warburg effect in the TME.81 These studies highlight the dual advantages of CDs as gas carriers and catalytic platforms; their abundant surface functional groups and tunable electronic structures provide a molecular basis for precise regulation in gas therapy.

Figure 8 (a) NO release from C-NO treated with different conditions. (b) Fluorescence images of DCFH-DA stained 4T1 cells under different conditions. Reproduced with permission.80 (c) Fluorescence images of HepG2 cells labeled with ROS, NO and ONOO− probes after irradiating with LED light (400–500 nm, 100 mW/cm2) for 12 min, scale bar = 100um. Reproduced with permission.82 (d) CLSM images of MCF-7 cells stained with the COP probe for CO detection (Scale bar is 20um). Reproduced with permission.135

Synergistic Integration Strategies of CDs with Multimodal Therapy

The versatility of CDs is further reflected in their synergistic integration with multimodal therapy. For instance, copper/nitrogen/sulfur co-doped carbon quantum dots (Cu,N,S-CQDs) catalyze H2O2 to generate hydroxyl radicals (·OH) via peroxidase-like activity, while simultaneously releasing hydrogen sulfide (H2S) gas and camptothecin (CPT). This achieves multi-effect synergy of chemodynamic therapy (CDT), GT, and chemotherapy.136 In another study, cetuximab-modified Ni/Mn-doped CDs (Cet-CDs-SNO) integrate near-infrared-II (NIR-II) photothermal therapy (PTT), NO gas release, and multimodal imaging functions. They enhance tumor cell apoptosis through heat-triggered NO release.137 More innovatively, as shown in Figure 8c, metformin-modified red-emitting CDs (MMCDs) utilize light-controlled NO release and lysosomal targeting properties. This enables in-situ reaction between NO and singlet oxygen (1O2) generated by photodynamics to form peroxynitrite (ONOO−), significantly increasing the killing efficiency of liver cancer cells to 80%.82 These designs break the limitations of single gas therapy through cascade catalysis, energy metabolism intervention (eg, glucose oxidase-mediated starvation therapy), and immune microenvironment regulation.

Spatiotemporally Controlled Gas Therapy

By developing smart responsive CD systems, precise spatiotemporal control of gas release is achieved. For example, Chen et al constructed mitochondria-targeted carbon dots (MitoCDs) conjugated with thermoresponsive nitric oxide (NO) donors. Under near-infrared (NIR) light control, this system achieves site-specific release of NO in mitochondria, and synergistically enhances photothermal therapeutic efficacy by disrupting energy metabolism.138 Metal-organic framework (MOF)-composite CD systems (eg, UiO-66-SH@FeCO) trigger CO release using H2O2 and ATP in the TME, while generating ·OH through Fenton reactions to form a reactive oxygen species (ROS)-CO synergistic killing effect.139 A more advanced study combines chemiluminescence (CL) with CD photocatalysis to construct a self-powered system (CuCN-L-MN). This system uses CL to activate CDs for in-situ reduction of CO2 to CO (Figure 8d) while simultaneously generating ROS, realizing closed-loop integration of non-invasive diagnosis and therapy.135 For this “self-powered in-situ gas generation” design, the matching between CO2 reduction efficiency and CO2 concentration at tumor sites still needs optimization, and few studies have reported differences in CO generation capacity of CDs across different tumor types.

Immunotherapy

Cancer immunotherapy is an innovative therapeutic approach that achieves antitumor effects by activating or enhancing the human immune system’s ability to recognize and kill tumor cells. Its core strategies include immune checkpoint inhibitors and tumor vaccines, which aim to break through the immunosuppressive barrier of the TME and restore immune responses.83 However, traditional immunotherapy often faces challenges such as insufficient immune activation, poor drug targeting, and systemic immune toxicity.

As emerging zero-dimensional carbon-based nanomaterials, CDs provide an intelligent delivery and synergistic regulation platform for immunotherapy due to their low toxicity, high stability, and multifunctional designability.84,140 Surface-engineered CDs can efficiently load immune-activating molecules (eg, cytokines, antigen peptides, or small-molecule agonists) and achieve precise delivery to lymph nodes or tumor sites via specific targeting ligands. Meanwhile, their unique photothermal/photodynamic properties can induce tumor immunogenic cell death (ICD) and release tumor antigens, thereby promoting antigen presentation and T cell activation. Further combination with immune checkpoint blockade enhances the antitumor immune cycle, ultimately advancing immunotherapy from a single-intervention model to a precise immune reg