Self‐Assembled Peptide‐Based Nanomaterials for Biomedical Imaging and Therapy

Peptide‐based materials are one of the most important biomaterials, with diverse structures and functionalities. Over the past few decades, a self‐assembly strategy is introduced to construct peptide‐based nanomaterials, which can form well‐controlled superstructures with high stability and multivalent effect. More recently, peptide‐based functional biomaterials are widely utilized in clinical applications. However, there is no comprehensive review article that summarizes this growing area, from fundamental research to clinic translation. In this review, the recent progress of peptide‐based materials, from molecular building block peptides and self‐assembly driving forces, to biomedical and clinical applications is systematically summarized. Ex situ and in situ constructed nanomaterials based on functional peptides are presented. The advantages of intelligent in situ construction of peptide‐based nanomaterials in vivo are emphasized, including construction strategy, nanostructure modulation, and biomedical effects. This review highlights the importance of self‐assembled peptide nanostructures for nanomedicine and can facilitate further knowledge and understanding of these nanosystems toward clinical translation.     

Peptide‐Based Nanotubes and Their Applications in Bionanotechnology

In nature, biological nanomaterials are synthesized under ambient conditions in a natural microscopic‐sized laboratory, such as a cell. Biological molecules, such as peptides and proteins, undergo self‐assembly processes in vivo and in vitro, and these monomers are assembled into various nanometer‐scale structures at room temperature and atmospheric pressure. The self‐assembled peptide nanostructures can be further organized to form nanowires, nanotubes, and nanoparticles via their molecular‐recognition functions. The application of molecular self‐assemblies of synthetic peptides as nanometer‐scale building blocks in devices is robust, practical, and affordable due to their advantages of reproducibility, large‐scale production ability, monodispersity, and simpler experimental methods. It is also beneficial that smart functionalities can be added at desired positions in peptide nanotubes through well‐established chemical and peptide syntheses. These features of peptide‐based nanotubes are the driving force for investigating and developing peptide nanotube assemblies for biological and non‐biological applications.     

Beta‐Sheet‐Forming,Self‐Assembled Peptide Nanomaterials towards Optical,Energy, and Healthcare Applications

Peptide self‐assembly is an attractive route for the synthesis of intricate organic nanostructures that possess remarkable structural variety and biocompatibility. Recent studies on peptide‐based, self‐assembled materials have expanded beyond the construction of high‐order architectures; they are now reporting new functional materials that have application in the emerging fields such as artificial photosynthesis and rechargeable batteries. Nevertheless, there have been few reviews particularly concentrating on such versatile, emerging applications. Herein, recent advances in the synthesis of self‐assembled peptide nanomaterials (e.g., cross β‐sheet‐based amyloid nanostructures, peptide amphiphiles) are selectively reviewed and their new applications in diverse, interdisciplinary fields are described, ranging from optics and energy storage/conversion to healthcare. The applications of peptide‐based self‐assembled materials in unconventional fields are also highlighted, such as photoluminescent peptide nanostructures, artificial photosynthetic peptide nanomaterials, and lithium‐ion battery components. The relation of such functional materials to the rapidly progressing biomedical applications of peptide self‐assembly, which include biosensors/chips and regenerative medicine, are discussed. The combination of strategies shown in these applications would further promote the discovery of novel, functional, small materials.     

Programmable Construction of Peptide‐Based Materials in Living Subjects: From Modular Design and Morphological Control to Theranostics

Self‐assembled nanomaterials show potential high efficiency as theranostics for high‐performance bioimaging and disease treatment. However, the superstructures of pre‐assembled nanomaterials may change in the complicated physiological conditions, resulting in compromised properties and/or biofunctions. Taking advantage of chemical self‐assembly and biomedicine, a new strategy of “in vivo self‐assembly” is proposed to in situ construct functional nanomaterials in living subjects to explore new biological effects. Herein, recent advances on peptide‐based nanomaterials constructed by the in vivo self‐assembly strategy are summarized. Modular peptide building blocks with various functions, such as targeting, self‐assembly, tailoring, and biofunctional motifs, are employed for the construction of nanomaterials. Then, self‐assembly of these building blocks in living systems to construct various morphologies of nanostructures and corresponding unique biological effects, such as assembly/aggregation‐induced retention (AIR), are introduced, followed by their applications in high‐performance drug delivery and bioimaging. Finally, an outlook and perspective toward future developments of in vivo self‐assembled peptide‐based nanomaterials for translational medicine are concluded.     

Near‐Infrared‐Light‐Activatable Nanomaterial‐Mediated Phototheranostic Nanomedicines: An Emerging Paradigm for Cancer Treatment

Cancer is one of the most deadly diseases threatening the lives of humans. Although many treatment methods have been developed to tackle cancer, each modality of cancer treatment has its own limitations and drawbacks. The development of minimally invasive treatment modalities for cancers remains a great challenge. Near‐infrared (NIR) light‐activated nanomaterial‐mediated phototherapies, including photothermal and photodynamic therapies, provide an alternative means for spatially and temporally controlled minimally invasive treatments of cancers. Nanomaterials can serve as nanocargoes for the delivery of chemo‐drugs, diagnostic contrast reagents, and organic photosensitizers, and can be used to directly generate heat or reactive oxygen species for the treatment of tumors without the need for organic photosensitizers with NIR‐light irradiation. Here, current progress in NIR‐light‐activated nanomaterial‐mediated photothermal therapy and photodynamic therapy is summarized. Furthermore, the effects of size, shape, and surface functionalities of nanomaterials on intracellular uptake, macrophage clearance, biodistribution, cytotoxicities, and biomedical efficacies are discussed. The use of various types of nanomaterials, such as gold nanoparticles, carbon nanotubes, graphene, and many other inorganic nanostructures, in combination with diagnostic and therapeutic modalities for solid tumors, is briefly reviewed.     

Self‐Assembling Endogenous Biliverdin as a Versatile Near‐Infrared Photothermal Nanoagent for Cancer Theranostics

Photothermal nanomaterials that integrate multimodal imaging and therapeutic functions provide promising opportunities for noninvasive and targeted diagnosis and treatment in precision medicine. However, the clinical translation of existing photothermal nanoagents is severely hindered by their unclear physiological metabolism, which makes them a strong concern for biosafety. Here, the utilization of biliverdin (BV), an endogenic near‐infrared (NIR)‐absorbing pigment with well‐studied metabolic pathways, to develop photothermal nanoagents with the aim of providing efficient and metabolizable candidates for tumor diagnosis and therapy, is demonstrated. It is shown that BV nanoagents with intense NIR absorption, long‐term photostability and colloidal stability, and high photothermal conversion efficiency can be readily constructed by the supramolecular multicomponent self‐assembly of BV, metal‐binding short peptides, and metal ions through the reciprocity and synergy of coordination and multiple noncovalent interactions. In vivo data reveal that the BV nanoagents selectively accumulate in tumors, locally elevate tumor temperature under mild NIR irradiation, and consequently induce efficient photothermal tumor ablation with promising biocompatibility. Furthermore, the BV nanoagents can serve as a multimodal contrast for tumor visualization through both photoacoustic and magnetic resonance imaging. BV has no biosafety concerns, and thereby offers a great potential in precision medicine by integrating multiple theranostic functions.     

Recent Advances in Cell Membrane–Camouflaged Nanoparticles for Cancer Phototherapy

Phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT) employs phototherapeutic agents to generate heat or cytotoxic reactive oxygen species (ROS), and has therefore garnered particular interest for cancer therapy. However, the main challenges faced by conventional phototherapeutic agents include easy recognition by the immune system, rapid clearance from blood circulation, and low accumulation in target sites. Cell‐membrane coating has emerged as a potential way to overcome these limitations, owing to the abundant proteins on the surface of cell membranes that can be inherited to the cell membrane–camouflaged nanoparticles. This review summarizes the recent advances in the development of biomimetic cell membrane–camouflaged nanoparticles for cancer phototherapy. Different sources of cell membranes can be used to coat nanoparticles uisng different coating approaches. After cell‐membrane coating, the photophysical properties of the original phototherapeutic nanoparticles remain nearly unchanged; however, the coated nanoparticles are equipped with additional physiological features including immune escape, in vivo prolonged circulation time, or homologous targeting, depending on the cell sources. Moreover, the coated cell membrane can be ablated from phototherapeutic nanoparticles under laser irradiation, leading to drug release and thus synergetic therapy. By combining other supplementary agents to normalize tumor microenvironment, cell‐membrane coating can further enhance the therapeutic efficacy against cancer.     

Flexible Photothermal Assemblies with Tunable Gold Patterns for Improved Imaging‐Guided Synergistic Therapy

Self‐assembly of gold nanoparticles demonstrates a promising approach to realize enhanced photoacoustic imaging (PAI) and photothermal therapy (PTT) for accurate diagnosis and efficient cancer therapy. Herein, unique photothermal assemblies with tunable patterns of gold nanoparticles (including arcs, rings, ribbons, and vesicles) on poly(lactic‐co‐glycolic acid) (PLGA) spheres are constructed taking advantage of emulsion‐confined and polymer‐directed self‐assembly strategies. The influencing factors and formation mechanism to produce the assemblies are investigated in details. Both the emulsion structure and migration behaviors of amphiphilic block copolymer tethered gold nanoparticles are found to contribute to the formation of versatile photothermal assemblies. Hyaluronic acid‐modified R‐PLGA‐Au (RPA) exhibits outstanding photothermal performances under NIR laser irradiation, which is induced by strong plasmonic coupling between adjacent gold nanoparticles. It is interesting that secondary assembly of RPA can be triggered by NIR laser irradiation. Prolonged residence time in tumors is achieved after RPA assemblies are fused into superstructures with larger sizes, realizing real‐time monitoring of the therapeutic processes via PAI with enhanced photoacoustic signals. Notably, synergistic effect resulting from PTT‐enhanced chemotherapy is realized to demonstrate high antitumor performance. This work provides a facile strategy to construct flexible photothermal assemblies with favorable properties for imaging‐guided synergistic therapy.     

Activating Antitumor Immunity and Antimetastatic Effect Through Polydopamine‐Encapsulated Core–Shell Upconversion Nanoparticles

Synergistic phototherapy has the potential to conquer the extreme heterogeneity and complexity of difficult tumors and result in better cancer treatment outcomes than monomodal photodynamic therapy (PDT) or photothermal therapy (PTT). However, the previous approaches to combining PDT and PTT are mainly focused on primary tumor obliteration while neglecting tumor metastasis, which is responsible for about 90% of cancer deaths. It is shown that a combined PDT/PTT approach, based on upconversion‐polymer hybrid nanoparticles with surface‐loaded chlorin e6 photosensitizer, can enhance primary tumor elimination and elicit antitumor immunity against disseminated tumors. The specifical arrangement of an external upconversion coating over the polymer core ensures adequate photoabsorption by the upconversion nanoparticles for the generation of reactive oxygen species upon single near‐infrared light irradiation. Furthermore, it is found that synergistic phototherapy can elicit robust systemic and humoral antitumor immune responses. When combined with immune checkpoint blockades, it can inhibit tumor relapse and metastasis as well as prolong the survival of tumor‐bearing mice in two types of tumor metastasis models. This study may establish a new modality for enhancing immunogenic cell death through a synergistic phototherapeutic nanoplatform and extend this strategy to overcome tumor metastasis with an augmented antitumor immune response.     

Dual‐Peak Absorbing Semiconducting Copolymer Nanoparticles for First and Second Near‐Infrared Window Photothermal Therapy: A Comparative Study

Near‐infrared (NIR) light is widely used for noninvasive optical diagnosis and phototherapy. However, current research focuses on the first NIR window (NIR‐I, 650–950 nm), while the second NIR window (NIR‐II, 1000–1700 nm) is far less exploited. The development of the first organic photothermal nanoagent (SPN_I‐II) with dual‐peak absorption in both NIR windows and its utilization in photothermal therapy (PTT) are reported herein. Such a nanoagent comprises a semiconducting copolymer with two distinct segments that respectively and identically absorb NIR light at 808 and 1064 nm. With the photothermal conversion efficiency of 43.4% at 1064 nm generally higher than other inorganic nanomaterials, SPN_I‐II enables superior deep‐tissue heating at 1064 nm over that at 808 nm at their respective safety limits. Model deep‐tissue cancer PTT at a tissue depth of 5 mm validates the enhanced antitumor effect of SPN_I‐II when shifting laser irradiation from the NIR‐I to the NIR‐II window. The good biodistribution and facile synthesis of SPN_I‐II also allow it to be doped with an NIR dye for fluorescence‐imaging‐guided NIR‐II PTT through systemic administration. Thus, this study paves the way for the development of new polymeric nanomaterials to advance phototherapy.     

Multifunctional Nanoparticles Self‐Assembled from Small Organic Building Blocks for Biomedicine

Supramolecular self‐assembly shows significant potential to construct responsive materials. By tailoring the structural parameters of organic building blocks, nanosystems can be fabricated, whose performance in catalysis, energy storage and conversion, and biomedicine has been explored. Since small organic building blocks are structurally simple, easily modified, and reproducible, they are frequently employed in supramolecular self‐assembly and materials science. The dynamic and adaptive nature of self‐assembled nanoarchitectures affords an enhanced sensitivity to the changes in environmental conditions, favoring their applications in controllable drug release and bioimaging. Here, recent significant research advancements of small‐organic‐molecule self‐assembled nanoarchitectures toward biomedical applications are highlighted. Functionalized assemblies, mainly including vesicles, nanoparticles, and micelles are categorized according to their topological morphologies and functions. These nanoarchitectures with different topologies possess distinguishing advantages in biological applications, well incarnating the structure–property relationship. By presenting some important discoveries, three domains of these nanoarchitectures in biomedical research are covered, including biosensors, bioimaging, and controlled release/therapy. The strategies regarding how to design and characterize organic assemblies to exhibit biomedical applications are also discussed. Up‐to‐date research developments in the field are provided and research challenges to be overcome in future studies are revealed.     

Dynamically PEGylated and Borate‐Coordination‐Polymer‐Coated Polydopamine Nanoparticles for Synergetic Tumor‐Targeted,Chemo‐Photothermal Combination Therapy

Multifunctional nanomaterials with efficient tumor‐targeting and high antitumor activity are highly anticipated in the field of cancer therapy. In this work, a synergetic tumor‐targeted, chemo‐photothermal combined therapeutic nanoplatform based on a dynamically PEGylated, borate‐coordination‐polymer‐coated polydopamine nanoparticle (PDA@CP‐PEG) is developed. PEGylation on the multifunctional nanoparticles is dynamically achieved via the reversible covalent interaction between the surface phenylboronic acid (PBA) group and a catechol‐containing poly(ethylene glycol) (PEG) molecule. Due to the acid‐labile PBA/catechol complex and the weak‐acid‐stable PBA/sialic acid (SA) complex, the nanoparticles can exhibit a synergetic targeting property for the SA‐overexpressed tumor cells, i.e., the PEG‐caused “passive targeting” and PBA‐triggered “active targeting” under the weakly acidic tumor microenvironment. In addition, the photothermal effect of the polydopamine core and the doxorubicin‐loading capacity of the porous coordination polymer layer endow the nanoparticles with the potential for chemo‐photothermal combination therapy. As expected, the in vitro and in vivo studies both verify that the multifunctional nanoparticles possess relatively lower systematic toxicity, efficient tumor targeting ability, and excellent chemo‐photothermal activity for tumor inhibition. It is believed that these multifunctional nanoparticles with synergetic tumor targeting property and combined therapeutic strategies would provide an insight into the design of a high‐efficiency antitumor nanoplatform for potential clinical applications.     

Synthesis of BSA‐Coated BiOI@Bi2S3 Semiconductor Heterojunction Nanoparticles and Their Applications for Radio/Photodynamic/Photothermal Synergistic Therapy of Tumor

Developing an effective theranostic nanoplatform remains a great challenge for cancer diagnosis and treatment. Here, BiOI@Bi₂S₃@BSA (bovine serum albumin) semiconductor heterojunction nanoparticles (SHNPs) for triple‐combination radio/photodynamic/photothermal cancer therapy and multimodal computed tomography/photoacoustic (CT/PA) bioimaging are reported. On the one hand, SHNPs possess strong X‐ray attenuation capability since they contain high‐Z elements, and thus they are anticipated to be a very competent candidate as radio‐sensitizing materials for radiotherapy enhancement. On the other hand, as a semiconductor, the as‐prepared SHNPs offer an extra approach for reactive oxygen species generation based on electron–hole pair under the irradiation of X‐ray through the photodynamic therapy process. This X‐ray excited photodynamic therapy obviously has better penetration depth in bio‐tissue. What's more, the SHNPs also possess well photothermal conversion efficiency for photothermal therapy, because Bi₂S₃ is a thin band semiconductor with strong near‐infrared absorption that can cause local overheat. In vivo tumor ablation studies show that synergistic radio/photodynamic/photothermal therapy achieves more significant therapeutic effect than any single treatment. In addition, with the strong X‐ray attenuation and high near‐infrared absorption, the as‐obtained SHNPs can also be applied as a multimodal contrast agent in CT/PA imaging.     

Supramolecular Protein Nanodrugs with Coordination‐ and Heating‐Enhanced Photothermal Effects for Antitumor Therapy

Supramolecular protein nanodrugs provide opportunities for improving antitumor therapeutic efficiency and lowering toxicity. However, protein nanodrugs that have robust structural stability and enhanced therapeutic efficiency are still in infancy. In this study, photothermal protein nanodrugs are constructed through a supramolecular approach along with heating by using proteins, photosensitizers, and metal ions as the building blocks. The metal coordination and heating improve not only the structural stability but also photothermal performance of the resulting nanodrugs. By virtue of the first integration of coordination‐ and heating‐enhanced photothermal effects, the nanodrugs show superior photothermal conversion efficiency, enhanced tumor accumulation, and improved tumor inhibition. Metal coordination and heating are versatile to be applied for various protein nanodrugs. Hence, this study provides insights for the construction of highly efficient photothermal nanodrugs and thus will be beneficial to precision theranostics.     

First Demonstration of Gold Nanorods‐Mediated Photodynamic Therapeutic Destruction of Tumors via Near Infra‐Red Light Activation

Previously, a large volume of papers reports that gold nanorods (Au NRs) are able to effectively kill cancer cells upon high laser doses (usually 808 nm, 1–48 W/cm²) irradiation, leading to hyperthermia‐induced destruction of cancer cells, i.e, photothermal therapy (PTT) effects. Combination of Au NRs‐mediated PTT and organic photosensitizers‐mediated photodynamic therapy (PDT) were also reported to achieve synergistic PTT and PDT effects on killing cancer cells. Herein, we demonstrate for the first time that Au NRs alone can sensitize formation of singlet oxygen (¹O₂) and exert dramatic PDT effects on complete destrcution of tumors in mice under very low LED/laser doses of single photon NIR (915 nm, <130 mW/cm²) light excitation. By changing the NIR light excitation wavelengths, Au NRs‐mediated phototherapeutic effects can be switched from PDT to PTT or combination of both. Both PDT and PTT effects were confirmed by measurements of reactive oxygen species (ROS) and heat shock protein (HSP 70), singlet oxygen sensor green (SOSG) sensing, and sodium azide quenching in cellular experiments. In vivo mice experiments further show that the PDT effect via irradiation of Au NRs by 915 nm can destruct the B16F0 melanoma tumor in mice far more effectively than doxorubicin (a clinically used anti‐cancer drug) as well as the PTT effect (via irradiation of Au NRs by 780 nm light). In addition, we show that Au NRs can emit single photon‐induced fluorescence to illustrate their in vivo locations/distribution.     

Multibuilding Block Janus Synthesized by Seed‐Mediated Self‐Assembly for Enhanced Photothermal Effects and Colored Brownian Motion in an Optical Trap

The asymmetrical features and unique properties of multibuilding block Janus nanostructures (JNSs) provide superior functions for biomedical applications. However, their production process is very challenging. This problem has hampered the progress of JNS research and the exploration of their applications. In this study, an asymmetrical multibuilding block gold/iron oxide JNS has been generated to enhance photothermal effects and display colored Brownian motion in an optical trap. JNS is formed by seed‐mediated self‐assembly of nanoparticle‐loaded thermocleavable micelles, where the hydrophobic backbones of the polymer are disrupted at high temperatures, resulting in secondary self‐assembly and structural rearrangement. The JNS significantly enhances photothermal effects compared to their homogeneous counterpart after near‐infrared (NIR) light irradiation. The asymmetrical distribution of gold and iron oxide within JNS also generates uneven thermophoretic force to display active colored Brownian rotational motion in a single‐beam gradient optical trap. These properties indicate that the asymmetrical JNS could be employed as a strong photothermal therapy mediator and a fuel‐free nanoscale Janus motor under NIR light.     

Self-Assembled Peptide-Based Nanodrugs: Molecular Design,Synthesis, Functionalization,and Targeted Tumor Bioimaging and Biotherapy

Functional nanomaterials as nanodrugs based on the self-assembly of inorganics, polymers, and biomolecules have showed wide applications in biomedicine and tissue engineering. Ascribing to the unique biological, chemical, and physical properties of peptide molecules, peptide is used as an excellent precursor material for the synthesis of functional nanodrugs for highly effective cancer therapy. Herein, recent progress on the design, synthesis, functional regulation, and cancer bioimaging and biotherapy of peptide-based nanodrugs is summarized. For this aim, first molecular design and controllable synthesis of peptide nanodrugs with 0D to 3D structures are presented, and then the functional customization strategies for peptide nanodrugs are presented. Then, the applications of peptide-based nanodrugs in bioimaging, chemotherapy, photothermal therapy (PTT), and photodynamic therapy (PDT) are demonstrated and discussed in detail. Furthermore, peptide-based drugs in preclinical, clinical trials, and approved are briefly described. Finally, the challenges and potential solutions are pointed out on addressing the questions of this promising research topic. This comprehensive review can guide the motif design and functional regulation of peptide nanomaterials for facile synthesis of nanodrugs, and further promote their practical applications for diagnostics and therapy of diseases.     

Photosensitizer‐Conjugated Albumin−Polypyrrole Nanoparticles for Imaging‐Guided In Vivo Photodynamic/Photothermal Therapy

Conjugated polymers with strong absorbance in the near‐infrared (NIR) region have been widely explored as photothermal therapy agents due to their excellent photostability and high photothermal conversion efficiency. Herein, polypyrrole (PPy) nanoparticles are fabricated by using bovine serum albumin (BSA) as the stabilizing agent, which if preconjugated with photosensitizer chlorin e6 (Ce6) could offer additional functionalities in both imaging and therapy. The obtained PPy@BSA‐Ce6 nanoparticles exhibit little dark toxicity to cells, and are able to trigger both photodynamic therapy (PDT) and photothermal therapy (PTT). As a fluorescent molecule that in the meantime could form chelate complex with Gd³⁺, Ce6 in PPy@BSA‐Ce6 nanoparticles after being labeled with Gd³⁺ enables dual‐modal fluorescence and magnetic resonance (MR) imaging, which illustrate strong tumor uptake of those nanoparticles after intravenous injection into tumor‐bearing mice. In vivo combined PDT and PTT treatment is then carried out after systemic administration of PPy@BSA‐Ce6, achieving a remarkably improved synergistic therapeutic effect compared to PDT or PTT alone. Hence, a rather simple one‐step approach to fabricate multifunctional nanoparticles based on conjugated polymers, which appear to be promising in cancer imaging and combination therapy, is presented.     

A Self‐Assembled DNA Origami‐Gold Nanorod Complex for Cancer Theranostics

A self‐assembled DNA origami (DO)‐gold nanorod (GNR) complex, which is a dual‐functional nanotheranostics constructed by decorating GNRs onto the surface of DNA origami, is demonstrated. After 24 h incubation of two structured DO‐GNR complexes with human MCF7 breast cancer cells, significant enhancement of cell uptake is achieved compared to bare GNRs by two‐photon luminescence imaging. Particularly, the triangle shaped DO‐GNR complex exhibits optimal cellular accumulation. Compared to GNRs, improved photothermolysis against tumor cells is accomplished for the triangle DO‐GNR complex by two‐photon laser or NIR laser irradiation. Moreover, the DO‐GNR complex exhibits enhanced antitumor efficacy compared with bare GNRs in nude mice bearing breast tumor xenografts. The results demonstrate that the DO‐GNR complex can achieve optimal two‐photon cell imaging and photothermal effect, suggesting a promising candidate for cancer diagnosis and therapy both in vitro and in vivo.     

Two‐Dimensional Nanomaterials for Cancer Nanotheranostics

Emerging nanotechnologies show unprecedented advantages in accelerating cancer theranostics. Among them, two‐dimensional nanomaterials (2DNMs) represent a novel type of material with versatile physicochemical properties that have enabled a new horizon for applications in both cancer diagnosis and therapy. Studies have demonstrated that 2DNMs may be used in diverse aspects, including i) cancer detection due to their high propensity towards tumor markers; ii) molecular imaging for guided tumor therapies, and iii) drug and gene loading, photothermal and photodynamic cancer therapies. However, their biomedical applications raise concerns due to the limited understanding of their in vivo metabolism, transformation and possible toxicities. In this comprehensive review, the state‐of‐the‐art development of 2DNMs and their implications for cancer nanotheranostics are presented. The modification strategies to enhance the biocompatibility of 2DNMs are also reviewed.