Structure‐Governed MXene Quantum Dots for Cancer Theranostics: From Quantum Confinement to Tumor‐Selective Catalytic and Photothermal Activation

Photothermal therapy (PTT) offers significant potential in cancer treatment due to its short, simple, and less harmful nature. However, obtaining a photothermal agent (PTA) with good photothermal performance and biocompatibility remains a challenge. MXenes, which are PTAs, have shown promising results in cancer treatment. This study presents the preparation of Ti3C2 MXene quantum dots (MXene QDs) using a simple hydrothermal and ultrasonic method and their use as a PTA for cancer treatment. Compared to conventional MXene QDs synthesized using only the hydrothermal method, the ultrasonic process increased the degree of oxidation on the surface of the MXene QDs. This resulted in the presence of more hydrophilic groups such as hydroxyl groups on the MXene QD surfaces, leading to excellent dispersion in the aqueous system and biocompatibility of the prepared MXene QDs without the need for surface modification. The MXene QDs showed great photothermal performance with a photothermal conversion efficiency of 62.5%, resulting in the highest photothermal conversion efficiency among similar materials reported thus far. Both in vitro and in vivo experiments have proved the potent tumor inhibitory effect of the MXene QD-mediated PTT, with minimal harm to mice. Therefore, these MXene QDs hold a significant promise for clinical applications.

Cancer remains a significant global health challenge, necessitating innovative therapeutic strategies. Functional organic luminogens have emerged as a versatile class of biomaterials for cancer theranostics, enabling the integration of diagnostic imaging and therapeutic intervention within a single molecular or supramolecular platform. In this perspective, recent advances in the rational design of these luminogens as next-generation cancer theranostics were discussed. Particular emphasis is placed on emerging organic luminogen systems, including aggregation-induced emission (AIE) small molecules, thermally activated delayed fluorescence (TADF)-based probes, polymer-based nanostructures, organic co-crystals, and charge-transfer (CT) assemblies, with an emphasis on their structure-property-function relationships. Unlike conventional nanoparticle systems, small-molecule luminogens have defined structures, improved biocompatibility, and faster clearance rates, enabling deeper tumor penetration and reduced long-term toxicity. Key molecular design strategies that regulate excited-state dynamics, aggregation behavior, charge transfer, and microenvironment responsiveness are discussed in the context of near-infrared (NIR) and NIR-II imaging, photodynamic and photothermal therapy, and synergistic multimodal treatments. Finally, challenges related to specificity, biosafety, and translational implementation are outlined, while emerging opportunities like data driven molecular discovery and artificial intelligence-assisted discovery are highlighted as future directions for the development of organic luminogens-based biomaterials in precision cancer theranostics.

Achieving precise cancer theranostics necessitates the rational design of smart nanosystems that ensure high biological safety and minimize non-specific interactions with normal tissues. In this regard, "bioinspired" membrane-coated nanosystems have emerged as a promising approach, providing a versatile platform for the development of next-generation smart nanosystems. This review article presents an in-depth investigation into the potential of these nanosystems for targeted cancer theranostics, encompassing key aspects such as cell membrane sources, isolation techniques, nanoparticle core selection, approaches for coating nanoparticle cores with the cell membrane, and characterization methods. Moreover, this review underscores strategies employed to enhance the multi-functionality of these nanosystems, including lipid insertion, membrane hybridization, metabolic engineering, and genetic modification. Additionally, the applications of these bioinspired nanosystems in cancer diagnosis and therapeutics are discussed, along with the recent advances in this field. Through a comprehensive exploration of membrane-coated nanosystems, this review provides valuable insights into their potential for precise cancer theranostics.

Cancer theranostics is a new concept of medical approach that attempts to combine in a unique nanoplatform diagnosis, monitoring and therapy so as to provide eradication of a solid tumor in a non-invasive fashion. There are many available solutions to tackle cancer using theranostic agents such as photothermal therapy (PTT) and photodynamic therapy (PDT) under the guidance of imaging techniques (e.g., magnetic resonance—MRI, photoacoustic—PA or computed tomography—CT imaging). Additionally, there are several potential theranostic nanoplatforms able to combine diagnosis and therapy at once, such as gold nanoparticles (GNPs), graphene oxide (GO), superparamagnetic iron oxide nanoparticles (SPIONs) and carbon nanodots (CDs). Currently, surface functionalization of these nanoplatforms is an extremely useful protocol for effectively tuning their structures, interface features and physicochemical properties. This approach is much more reliable and amenable to fine adjustment, reaching both physicochemical and regulatory requirements as a function of the specific field of application. Here, we summarize and compare the most promising metal- and carbon-based theranostic tools reported as potential candidates in precision cancer theranostics. We focused our review on the latest developments in surface functionalization strategies for these nanosystems, or hybrid nanocomposites consisting of their combination, and discuss their main characteristics and potential applications in precision cancer medicine.

Atomic-level structural engineering represents a powerful paradigm for tailoring layered nanomaterials (LNs) toward advanced cancer theranostics, enabling precise control of physicochemical properties to overcome the limitations of conventional nanoplatforms. This review provides a comprehensive overview of the latest advances in engineering LNs, including layered metal oxides, layered double hydroxides, transition metal dichalcogenides, graphene, layered silicates, graphitic carbon nitride, metal carbides and nitrides, and other layered frameworks for cancer diagnosis and therapy. Five representative atomic-level engineering strategies are discussed, including crystal phase engineering, defect engineering, heteroatom doping, interlayer spacing engineering, and crystalline-to-amorphous phase engineering. For each strategy, the underlying mechanisms, representative synthetic approaches, and their roles in optimizing theranostic performance, such as photothermal conversion, reactive oxygen species generation, and multimodal imaging, are critically discussed. Crucially, the advantages and inherent limitations of these engineering strategies are comparatively evaluated to provide a balanced perspective on their practical applicability. Finally, key challenges toward clinical translation, including structural stability, biosafety, and scalability, are highlighted. Future directions are proposed for developing intelligent, adaptive, and personalized LN-based nanomedicines for precision oncology.

Breast cancer is one of the most frequently diagnosed cancers in women and the major cause of worldwide cancer-related deaths among women. Various treatment strategies including conventional chemotherapy, immunotherapy, gene therapy, gene silencing and deliberately engineered nanomaterials for receptor mediated targeted delivery of anticancer drugs, antibodies, and small-molecule inhibitors, etc are being investigated by scientists to combat breast cancer. Smartly designed/fabricated nanomaterials are being explored to target breast cancer through enhanced permeation and retention effect; and also, being conjugated with suitable ligand for receptor-mediated endocytosis to target breast cancer for diagnostic, and theranostic applications. These receptor-targeted nanomedicines have shown efficacy to target specific tumor tissue/cells abstaining the healthy tissues/cells from cytotoxic effect of anticancer drug molecules. In the last few decades, theranostic nanomedicines have gained much attention among other nanoparticle systems due to their unique ability to deliver chemotherapeutic as well as diagnostic agents, simultaneously. Theranostic nanomaterials are emerging as novel paradigm with ability for concurrent delivery of imaging (with contrasting agents), targeting (with biomarkers), and anticancer therapeutics with one delivery system (as cancer theranostics) and can transpire as promising strategy to overcome various hurdles for effective management of breast cancer including its most aggressive form, triple-negative breast cancer.

Despite the development of medical technology, cancer still remains a great threat to the survival of people all over the world. Photothermal therapy (PTT) is a minimally invasive method for selective photothermal ablation of cancer cells without damages to normal cells. Recently, copper chalcogenide semiconductors have emerged as a promising photothermal agent attributed to strong absorbance in the near-infrared (NIR) region and high photothermal conversion efficiency. An earlier study witnessed a rapid increase in their development for cancer therapy, including CuS, Cu2-xSe and CuTe nanocrystals. However, a barrier is that the minimum laser power intensity for effective PTT is still significantly higher than the conservative limit for human skin exposure. Improving the photothermal conversion efficiency and reducing the laser power density has become a direction for the development of PTT. Furthermore, in an effort to improve the therapeutic efficacy, many multimode therapeutic nanostuctures have been formulated by integrating the photothermal agents with antitumor drugs, photosensitizers, or radiosensitizers, resulting in a synergistic effect. Various functional materials also have been absorbed, attached, encapsulated, or coated on the photothermal nanostructures, including fluorescence, computed tomography, magnetic resonance imaging, realizing cancer diagnosis, tumor location, site-specific therapy, and evaluation of therapeutic responses via incorporation of diagnosis and treatment. In this Account, we present an overview of the NIR-responsive photothermal semiconductor nanomaterials for cancer theranostics with a focus on their design and functionalization based on our own work. Our group has developed a series of chalcogenides with greatly improved NIR photoabsorption as photothermal agents, allowing laser exposure within regulatory limits. We also investigated the photothermal bioapplications of hypotoxic oxides including WO3-x, MoO3-x, and RuO2, expanding their applications into a new field of photothermal materials. Furthermore, considering a much more enhanced therapeutic effect of multifunctional nanoagents, our group elaborately designed many nanocomposites, such as core-shell nanoparticles of Fe3O4@Cu2-xS and Cu9S5@mSiO2, based on the integration of photothermal agents with contrast agents or other anticancer medicines, achieving cancer theranostic and synergistic treatment. Ternary compound nanocrystals were also prepared with synthetic simplicity for multimodal imaging-guided therapy for cancer. This Account summarizes our past work, including the design and concept, synthesis, and characterization for in vitro and in vivo applications. Then, we analyzed the tendencies of the NIR-responsive photothermal semiconductor nanomaterials for clinical applications, highlighting their prospects and challenges. We believe that the photothermal technology from the NIR-responsive photothermal semiconductor nanomaterials would promote cancer theranostics to result in giant strides forward in the future.

Exploitation of stimuli-responsive nanoplatforms is of great value for precise and efficient cancer theranostics. Herein, an in situ activable “nanocluster-bomb” detonated by endogenous overexpressing legumain is fabricated for contrast-enhanced tumor imaging and controlled gene/drug release. By utilizing the functional peptides as bioligands, TAMRA-encircled gold nanoclusters (AuNCs) endowed with targeting, positively charged and legumain-specific domains are prepared as quenched building blocks due to the AuNCs' nanosurface energy transfer (NSET) effect on TAMRA. Importantly, the AuNCs can shelter therapeutic cargos of DNAzyme and Dox (Dzs-Dox) to aggregate larger nanoparticles as a “nanocluster-bomb” (AuNCs/Dzs-Dox), which could be selectively internalized into cancer cells by integrin-mediated endocytosis and in turn locally hydrolyzed in the lysosome with the aid of legumain. A “bomb-like” behavior including “spark-like” appearance (fluorescence on) derived from the diminished NSET effect of AuNCs and cargo release (disaggregation) of Dzs-Dox is subsequently monitored. The results showed that the AuNC-based disaggregation manner of the “nanobomb” triggered by legumain significantly improved the imaging contrast due to the activable mechanism and the enhanced cellular uptake of AuNCs. Meanwhile, the in vitro cytotoxicity tests revealed that the detonation strategy based on AuNCs/Dzs-Dox readily achieved efficient gene/chemo combination therapy. Moreover, the super efficacy of combinational therapy was further demonstrated by treating a xenografted MDA-MB-231 tumor model in vivo. We envision that our multipronged design of theranostic “nanocluster-bomb” with endogenous stimuli-responsiveness provides a novel strategy and great promise in the application of high contrast imaging and on-demand drug delivery for precise cancer theranostics.

Endogenous tumor microenvironment-responsive multifunctional nanoplatforms for precision cancer theranostics

Photothermal conversion is a growing research area that promotes thermal transformations with visible light irradiation. However, few examples of dual photothermal conversion and catalysis limit the power of this phenomenon. Here, we take inspiration from nature's ability to use porphyrinic compounds for nonradiative relaxation to convert light into heat to facilitate thermal polymerization catalysis. We identify the photothermal conversion catalytic activity of a vitamin B12 derivative, heptamethyl ester cobyrinate (HME-Cob), to perform atom transfer radical polymerization (ATRP) under irradiation. Rapid polymerization are obtained under photothermal activation while maintaining good control over polymerization with the aid of a photoinitiator to enable light-induced catalyst regeneration. The catalyst exhibits exquisite temporal control in photocontrolled thermal polymerization. Ultimately, the activation of this complex is accessed across a broad range of wavelengths, including near-IR light, with excellent temporal control. This work showcases the potential of developing photothermal conversion catalysts.

Bioactive materials are a special class of biomaterials that can react in vivo to induce a biological response or regulate biological functions, thus achieving a better curative effect than traditional inert biomaterials. For cancer theranostics, compared with organic or polymer nanomaterials, inorganic nanomaterials possess unique physical and chemical properties, have stronger mechanical stability on the basis of maintaining certain bioactivity, and are easy to be compounded with various carriers (polymer carriers, biological carriers, etc.), so as to achieve specific antitumor efficacy. After entering the nanoscale, due to the nano-size effect, high specific surface area and special nanostructures, inorganic nanomaterials exhibit unique biological effects, which significantly influence the interaction with biological organisms. Therefore, the research and applications of bioactive inorganic nanomaterials in cancer theranostics have attracted wide attention. In this review, we mainly summarize the recent progress of bioactive inorganic nanomaterials in cancer theranostics, and also introduce the definition, synthesis and modification strategies of bioactive inorganic nanomaterials. Thereafter, the applications of bioactive inorganic nanomaterials in tumor imaging and antitumor therapy, including tumor microenvironment (TME) regulation, catalytic therapy, gas therapy, regulatory cell death and immunotherapy, are discussed. Finally, the biosafety and challenges of bioactive inorganic nanomaterials are also mentioned, and their future development opportunities are prospected. This review highlights the bioapplication of bioactive inorganic nanomaterials.

Shattering kinetic constraints: hierarchically activatable DNAzyme nanoantennas for in situ mRNA imaging and precise cancer theranostics.

Cancer has been one of the most dreaded diseases, claiming millions of deaths worldwide. Malignant tumors are very difficult to treat due to the inherent limitations of traditional surgery and insensitivity to radiation and chemotherapy. However, in recent years, nanotechnology-based advanced techniques have been widely used for the early diagnosis and treatment of cancer. Thus, theranostic nanoparticle-based novel approaches are under extensive investigation for effective cancer diagnosis and therapy. In this chapter, different types of theranostic nanomaterials such as magnetic, carbon/silica, metallic and polymeric nanoparticles, and their synthesis procedures are initially described. Then, nanoparticle-based different imaging techniques, including magnetic resonance imaging (MRI), fluorescence/optical imaging, photoacoustic imaging, etc., have been elaborated. Besides, nanoparticle-based different therapeutic approaches, including magnetic hyperthermia therapy (MHT), photodynamic therapy (PDT), and photothermal therapy (PTT), have been explicated. Moreover, the applications of important theranostic nanomaterials such as superparamagnetic iron oxide nanoparticles (SPIONs), quantum dots (QDs), gold nanoparticles (AuNPs), and carbon nanotubes (CNTs) for the treatment of cancer are elucidated. Furthermore, the utilization of nanomaterials for effective multimodal imaging and therapy in cancer theranostics is expounded. Finally, the future prospects in the field of cancer theranostics are illuminated for the imminent knowledge of the readers. In summary, theranostic nanomaterials have immense potential in clinical diagnosis and therapeutics due to their unique intrinsic properties, making them favorable for effective cancer treatment.KeywordsTheranostic nanoparticlesCancer treatmentMagnetic resonance imaging (MRI)Magnetic particle imaging (MPI)Fluorescence imagingPhotoacoustic imagingPositron emission tomography (PET)ChemotherapyMagnetic hyperthermia therapy (MHT)Photothermal therapy (PTT)Photodynamic therapy (PDT)Multimodal imagingMultimodal therapy

Functional gadolinium-based nanoscale systems for cancer theranostics

Chapter 8 - Silver and gold nanoparticles: Potential cancer theranostic applications, recent development, challenges, and future perspectives