Stimuli‐Responsive Nanotheranostics
Authors: Yanglong Hou, Wenbo Bu, Hua Ai, Zheng‐Rong Lu, Twan Lammers
Journal: Advanced Healthcare Materials (2021)

In recent decades, the incidence of cancer has increased significantly, which proves to be a great threaten to human life, and brings heavy burden and pain to individuals, families, and society. With the cross-fusion of traditional medical imaging and targeting technology, molecular imaging has been expected to help the non-invasive and quantitative observation of cancer cell occurrence, development and metastasis at the cellular and molecular level, which is conducive to the grasp of cancer activity in vivo, and also to diagnose cancer as early as possible. Moreover, thanks to the combined therapy of surgery, radiotherapy, chemotherapy and immunotherapy, better treatment and improved overall efficacy have been achieved up to now. As a result, more lives can be saved and quality of life can be improved. However, one big challenge remaining now is the responsive evaluation of therapy. To date, it is hard to estimate the curing effects exactly, nor the appropriate dosage that is needed to be applied. Consequently, it is difficult to adjust the treatment plan in a truly personalized manner. Theranostics, with simultaneously therapeutic and diagnostic functions, is arguably of greatest help in patient stratification and treatment selection. Meanwhile, considering the rapid development of nanomedicine in addressing biomedical challenges, nanotheranostics—that possesses the advantages of both theranostics and nanomedicine—has achieved a leap forward in development in recent years. With the help of nanotheranostic agents, the effect information can be fed back to a treatment plan in time for the guidance of medication. In addition, the real-time impact of nanotheranostics can be further augmented by introducing some exogenous or endogenous stimuli. Therefore, these agents are able to control the biodistribution of these stimuli-responsive nanotheranostics, with enhanced safety and efficacy, by releasing the payload only at the site where it is needed, and provide specific imaging for better monitoring of the treatment response. This special issue on “Stimuli-Responsive Nanotheranostics” is assembled to recognize recent progress in the design and fabrication of novel stimuli-responsive nanoagents for application in disease diagnosis and therapy. Their influence on pathological microenvironments in vivo are also addressed. This special issue includes 11 review articles and four original papers, contributed by world-leading researchers, which broadly cover various important topics within this area. It is widely accepted that the tumor microenvironment (TME) presents different characteristics compared with normal tissues, such as a mildly acidic environment, hypoxia, overproduction of various enzymes, and a higher level of reactive oxygen species. These distinct physiological features can be exploited as internal stimuli for cancer-specific theranostics. For example, considering that hypoxia would lead to a sharp reduction in the drug delivery efficiency, Chunying Chen et al. provide a novel solution by using hypoxia-responsive theranostic agents (article number 2001277). They highlight the design principles, research progress, current limitations, and prospects for hypoxia-responsive nanotheranostic agents in tumor treatment. To solve the delivery problem associated with therapeutic RNA interference, environment-responsive lipids are proposed as carriers for siRNA. These lipids are able to respond to environmental changes in cancer during the delivery process, and thereby facilitate efficient cytosolic siRNA delivery to silence target genes for cancer treatment (article number 2001294). Certain smart nanomaterials can respond to more than one stimulus in the TME. These nanoagents can control drug release more intelligently. Won Jong Kim et al. reviewed the design strategies, challenges and critical considerations for nanocarriers that are sensitive to TME for more efficient tumor therapy (article number 2000834). In addition to improving therapeutic effects, TME-responsive nanomaterials are also beneficial for enhancing the target-to-background ratio of imaging probes. Weibo Cai et al. summarize recent developments on internally responsive multimodal nanoagents that can improve noninvasive cancer diagnosis and monitor drug delivery and treatment response (article number 2000690). Some recent research also suggested that the TME is important for tumor proliferation, invasion and metastasis. Therefore, understanding the details, accurate monitoring and even altering TME are essential, and are expected to provide guidance for effective personalized tumor treatment. Wenbo Bu et al. found that some TME-responsive functional computed tomography (CT) contrast nanoagents (FCTNAs) are able to diagnose TME precisely through taking advantage of features such as overexpressed receptors, acidic microenvironment, overexpressed glutathione and enzymes, and hypoxia. These FCTNAs could cause significant changes in the CT value under the tumor-specific environment for the sensitive monitoring of TME (article number 2000912). Recently, some kinds of enzymes were reported to have the capability of modulating the TME. Zhuang Liu et al. present a novel enhanced cancer treatment method by using enzyme nanoreactors for attenuating tumor hypoxia, modulating extracellular matrix, and amplifying tumor oxidative stress (article number 2001167). Cancer immunotherapy is booming as a new anti-cancer treatment strategy by activating the patients’ own immune system. Considering the intrinsic immunogenicity, as well as the delivery function and intelligent targeting of engineered nanoparticles (NPs), they are emerging as promising therapeutic agents to enhance conventional immunotherapy, as described by Yanglong Hou et al. (article number 2000845). Apart from tumors with their special microenvironment, other diseases such as inflammation and stroke are also featured with unique environment. These characteristics can be used as endogenous stimuli for selective theranostics. Considering the phenotypic imbalance between M1 and M2 macrophages induced by inflammation-related disorders, and the propensity of gold nanomaterials with different physicochemical characteristics to modulate macrophage polarization, Ya Ding et al. review the applications of gold-based nanomaterials in tracking and treating inflammatory diseases (article number 2000818). Another example comes from Qiangbin Wang's group (article number 2001544), taking advantage of the prodromal biomarker of ischemic stroke (i.e., peroxynitrite) that can induce Cy7.5 oxidation. They developed a new nanoprobe for the highly sensitive and real-time detection of early ischemic stroke based on Cy7.5-conjugated quantum dots (QDs). The origin state for the probe is “off” due to the competitive absorption of excitation irradiation between Cy7.5 and QDs. The fluorescence could only be activated by the targeting of NPs to the inflamed vascular endothelium of ischemic stroke based on VCAM1 binding peptide, accompanied by the oxidation of Cy7.5 to light up the stroke regions. Additionally, bioorthogonal chemistry is an emerging tool for the generation of imaging and therapeutic agents inside living systems, providing a promising strategy for controlled in situ activation of prodyes and prodrugs for nanotheranostics. In this context, Vincent Rotello et al. report novel bioorthogonal “polyzymes” that are composed of ruthenium-based catalysts encapsulated in a polymeric scaffold, protecting the catalytic centers from deactivation in biological media, efficiently activating pro-fluorophores, and transforming a substantially less toxic prodrug to an anticancer drug in cancer cells (article number 2001627). Besides endogenous stimuli, also exogenous stimuli are extensively applied for more controllable theranostics. Light is one of the most flexible exogenous stimuli for on-demand theranostics by realizing controlled drug delivery, photothermia and photodynamic therapy. However, despite significant progress achieved, sequential liberation of the same or different drug in multiple time from a single nanoparticle has remained a challenge in light-controlled drug release. Gang Han's group developed a novel light-controlled drug carrier based on gold NPs that wavelength-selectively and sequentially photolyzed two payloads in living cells, providing a new tool for more orderly controlling cellular events (article number 2000321). The limitation of light-related theranostics is the poor tissue penetration of light, making it difficult to reach deep tissues. Magnetic fields have deep tissue penetration and therefore serve as promising stimuli for on-demand nanotheranostics. Iron oxide is a typical magnetic nanomaterial with powerful capabilities to “seek, sense, and attack” diseased components with the assistance of a magnetic field. Stathis Karathanasis et al. give a summary on the rationale for and recent advances in the application of iron oxide NPs as stimuli-responsive nanotheranostics (article number 2001044). Magnetic resonance imaging (MRI) is a widely applied disease diagnosis tool based on magnetic fields. Recently developed stimuli-responsive MRI contrast agents could alter the relaxation signal in response to the environment change, which can reflect the physiological and pathological conditions of the site of interest. For this reason, Hua Ai et al. comprehensively discuss the strategies of designing stimuli-responsive MRI contrast agents (2001091). Radioactive rays have emerged as another kind of external stimulus for theranostics in deep tissues. Radionuclides with Cerenkov radiation are developed as a specific kind of radiation that can serve as an excitation source to activate photosensitizers for imaging, photodynamic therapy, and radiotherapy (article number 2000802). Additionally, some polymers are capable of conformational and chemical changes upon excitation with external stimuli, making them appealing candidates for fabricating stimuli-responsive nanotheranostic agents. Responsive polymer brushes are a typical example, whose responsiveness can be tuned by brush thickness, density, chemistry, and architecture. Julien Gautrot et al. review the design, synthesis and usage of responsive polymer brushes as novel biosensors and diagnostic tools for the detection of analytes and biomarkers (article number 2000953). Taken together, the publications presented in this special issue exemplify the recent progress in stimuli-responsive nanotheranostics. These are a small embodiment of the efforts invested in this exciting research field. We hope this special issue will bridge fundamental studies with clinical translation and serve as a promotor to encourage more experts to get involved in the near future. We would like to thank all the authors for their invaluable support in shaping this special issue, as well as those whose work could not be included due to space constraints. We furthermore gratefully acknowledge Dr. Jing Zhu for her support throughout the process of creating this special issue. Yanglong Hou earned his Ph.D. in materials science from Harbin Institute of Technology (P. R. China) in 2000. After a short postdoctoral training at Peking University, he worked at the University of Tokyo between 2002–2005 as a JSPS foreign special researcher and also at Brown University between 2005–2007 as a postdoctoral researcher. He joined Peking University in 2007 and is now a professor of materials science. His research interests include the design and chemical synthesis of functional nanoparticles, and their biomedical and energy-related applications. Wenbo Bu received his Ph.D. degree at Nanjing University of Technology. He is a full professor at Fudan University and an adjunct professor at the Shanghai Institute of Ceramics, Chinese Academy of Sciences (SICCAS). His current research interests include the design and synthesis of multifunctional nanomaterials for cancer imaging and therapeutic applications. Hua Ai, professor of biomaterials, National Engineering Research Center for Biomaterials, Sichuan University (SCU); adjunct professor of radiology, West China Hospital, SCU. Hua Ai focuses on the design and application of magnetic nanobiomaterials for molecular imaging and drug delivery. He developes sensitive magnetic resonance imaging (MRI) probes based on superparamagnetic iron oxide nanoparticles and paramagnetic molecules. Most of his work is carried out under clinical MRI scanners. Zheng-Rong Lu is M. Frank Rudy and Margaret Domiter Rudy Professor at the Department of Biomedical Engineering, Case Western Reserve University. He received his B.S. and M.S. in chemistry from Lanzhou University, and Ph.D. in chemistry from Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences at Lanzhou, China. In 1992, he was associate professor of chemistry and became professor in 1993 at Wuhan University, China. He was assistant professor in the Department of Pharmaceutics and Pharmaceutical Chemistry at the University of Utah in 2002 and associate professor in 2006. He has been in CWRU since 2009. His research efforts involve molecular imaging, novel MRI contrast agents, multifunctional amino lipids nonviral gene delivery, and gene therapy. Twan Lammers obtained a D.Sc. in radiation oncology from Heidelberg University in 2008 and a Ph.D. in pharmaceutics from Utrecht University in 2009. In the same year, he started the Nanomedicine and Theranostics group at RWTH Aachen University Clinic. In 2014, he was promoted to full professor of medicine. His research focuses on image-guided drug delivery, as well as on materials and methods to monitor tumor growth, angiogenesis, inflammation, fibrosis, and metastasis. He has received several awards, including the young investigator award of the Controlled Release Society.