Advances in Nanodynamic Therapy for Cancer Treatment.

Nanodynamic therapy (NDT) exerts its anti-tumor effect by activating nanosensitizers to generate large amounts of reactive oxygen species (ROS) in tumor cells. NDT enhances tumor-specific targeting and selectivity by leveraging the tumor microenvironment (TME) and mechanisms that boost anti-tumor immune responses. It also minimizes damage to surrounding healthy tissues and enhances cytotoxicity in tumor cells, showing promise in cancer treatment, with significant potential. This review covers the research progress in five major nanodynamic therapies: photodynamic therapy (PDT), electrodynamic therapy (EDT), sonodynamic therapy (SDT), radiodynamic therapy (RDT), and chemodynamic therapy (CDT), emphasizing the significant role of advanced nanotechnology in the development of NDT for anti-tumor purposes. The mechanisms, effects, and challenges faced by these NDTs are discussed, along with their respective solutions for enhancing anti-tumor efficacy, such as pH response, oxygen delivery, and combined immunotherapy. Finally, this review briefly addresses challenges in the clinical translation of NDT.

Optimized strategies of ROS-based nanodynamic therapies for tumor theranostics.

Reactive oxygen species (ROS) play a crucial role in regulating the metabolism of tumor growth, metastasis, death and other biological processes. ROS-based nanodynamic therapies (NDTs) are becoming attractive due to non-invasive, low side effects and tumor-specific advantages. NDTs have rapidly developed into numerous branches, such as photodynamic therapy, chemodynamic therapy, sonodynamic therapy and so on. However, the complexity of the tumor microenvironment and the limitations of existing sensitizers have greatly restricted the therapeutic effects of NDTs, which heavily rely on ROS levels. To address the limitations of NDTs, various strategies have been developed to increase ROS yield, which is an urgent aspect for the positive development of NDTs. In this review, the nanodynamic potentiation strategies in terms of unique properties and universalities of NDTs are comprehensively outlined. We mainly summarize the current dilemmas faced by each NDT and the respective solutions. Meanwhile, the NDTs universalities-based potentiation strategies and NDTs-based combined treatments are elaborated. Finally, we conclude with a discussion of the key issues and challenges faced in the development and clinical transformation of NDTs.

Reticular Chemistry-Enabled Sonodynamic Activity of Covalent Organic Frameworks for Nanodynamic Cancer Therapy.

The development of covalent organic framework (COF) sonosensitizers with intrinsic sonodynamic effects is highly desirable. However, such COFs are generally constructed using small-molecule photosensitizers. Herein, we report that the reticular chemistry-based synthesis of COFs from two inert monomers yields a COF-based sonosensitizer (TPE-NN) with inherent sonodynamic activity. Subsequently, a nanoscale COF TPE-NN is fabricated and embedded with copper (Cu)-coordinated sites to obtain TPE-NN-Cu. Results show that Cu coordination can enhance the sonodynamic effect of TPE-NN, whereas ultrasound (US) irradiation for sonodynamic therapy can augment the chemodynamic efficacy of TPE-NN-Cu. Consequently, TPE-NN-Cu upon US irradiation shows high-performance anticancer effects based on mutually reinforced sono-/chemo-nanodynamic therapy. This study reveals the backbone-originated sonodynamic activity of COFs and proposes a paradigm of intrinsic COF sonosensitizers for nanodynamic therapy.

A Sonication-Activated Valence-Variable Sono-Sensitizer/Catalyst for Autography Inhibition/Ferroptosis-Induced Tumor Nanotherapy.

The effective deployment of reactive oxygen species (ROS)-mediated oncotherapy in practice remains challenging, mired by uncontrollable catalytic processes, stern reaction conditions and safety concerns. Herein, we develop a copper nanodot integrating sonodynamic and catalytic effects within one active center, which responds to exogenous ultrasound (US) and endogenous H2 O2 stimuli. US irradiation induces the valence conversion from CuII to CuI catalyzing H2 O2 into ⋅OH for chemodynamic therapy. Meanwhile, valence transformation results in electron-hole pairs separation, promoting ROS generation for sonodynamic therapy. Notably, copper nanodots not only block lysosome fusion and degradation leading to autophagy flux blockage, but also interfere with the glutathione peroxidase 4 and cystine-glutamate antiporter SLC7A11 function achieving ferroptosis. Furthermore, reversible valence changes, inherent hydrophilicity and renal clearance ultrasmall size guarantee biosafety.

Microorganism-enabled photosynthetic oxygeneration and ferroptosis induction reshape tumor microenvironment for augmented nanodynamic therapy.

Nanodynamic therapy (NDT) based on reactive oxygen species (ROS) generation has been envisioned as a distinct modality for efficient cancer treatment. However, insufficient ROS generation and partial ROS consumption frequently limit the theraputic effect and outcome of NDT owing to the low oxygen (O2) tension and high glutathione (GSH) level in tumor microenvironment (TME). To circumvent these critical issues, we herein proposed and engineered the biodegradable GSH-depletion Mn(III)-riched manganese oxide nanospikes (MnOx NSs) with the photosynthetic bacterial cyanobacteria (Cyan) as a high-efficient and synergistic platform to reshape TME by simultaneously increasing oxygen content and decreasing GSH level. Specifically, under the trigger of acidity, MnOx NSs reacted with photosynthetic oxygen can generate toxic singlet oxygen (1O2). Moreover, MnOx NSs significantly reduced intracellular GSH, resulting in decreased GPX4 activity, which induced tumor cell non-apoptotic ferroptosis. Consequently, this combined strategy based on coadministration with Cyan and MnOx NSs demonstrated the superior antitumor efficacy via amplification of oxidative stress in 4T1 tumor-bearing mice for the synergetic oxygen-augmented nanodynamic/ferroptosis therapy. This work highlights a facile synergistic micro-/nano-system with the specific capability of reshaping TME to augment the sensitivity and therapeutic efficacy of NDT in solid hypoxic tumor therapy.

Emerging Nanomedicine-Enabled/Enhanced Nanodynamic Therapies beyond Traditional Photodynamics.

The rapid knowledge growth of nanomedicine and nanobiotechnology enables and promotes the emergence of distinctive disease-specific therapeutic modalities, among which nanomedicine-enabled/augmented nanodynamic therapy (NDT), as triggered by either exogenous or endogenous activators on nanosensitizers, can generate reactive radicals for accomplishing efficient disease nanotherapies with mitigated side effects and endowed disease specificity. As one of the most representative modalities of NDT, traditional light-activated photodynamics suffers from the critical and unsurmountable issues of the low tissue-penetration depth of light and the phototoxicity of the photosensitizers. To overcome these obstacles, versatile nanomedicine-enabled/augmented NDTs have been explored for satisfying varied biomedical applications, which strongly depend on the physicochemical properties of the involved nanomedicines and nanosensitizers. These distinctive NDTs refer to sonodynamic therapy (SDT), thermodynamic therapy (TDT), electrodynamic therapy (EDT), piezoelectric dynamic therapy (PZDT), pyroelectric dynamic therapy (PEDT), radiodynamic therapy (RDT), and chemodynamic therapy (CDT). Herein, the critical roles, functions, and biological effects of nanomedicine (e.g., sonosensitizing, photothermal-converting, electronic, piezoelectric, pyroelectric, radiation-sensitizing, and catalytic properties) for enabling the therapeutic procedure of NDTs, are highlighted and discussed, along with the underlying therapeutic principle and optimization strategy for augmenting disease-therapeutic efficacy and biosafety. The present challenges and critical issues on the clinical translations of NDTs are also discussed and clarified.