Guizhi Zhu

• PhD
• Professor (Associate) at University of Michigan

Introduction Protein/peptide vaccines show great promise for combination tumor immunotherapy with immune checkpoint blockade (ICB). However, conventional protein/peptide vaccines often elicit insufficient antitumor T cell responses, resulting in suboptimal therapeutic outcomes. Here, we introduced proteolysis-targeting vaccines (PROTAVs), which int...

Cancer immunotherapy is poised to be one of the major modalities for cancer treatment. Messenger RNA (mRNA) has emerged as a versatile and promising platform for the development of effective cancer immunotherapy. Delivery systems for mRNA therapeutics are pivotal for their optimal therapeutic efficacy and minimal adverse side effects. Lipid nanopar...

Protein/peptide vaccines can improve the tumor therapeutic efficacy of immune checkpoint blockade (ICB). However, current protein/peptide vaccines elicit limited T cell responses pivotal for tumor immunotherapy. Here, we present proteolysis-targeting vaccines (PROTAVs) that facilitate antigen proteolytic processing and cross-presentation to potenti...

Activating cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) holds great potential for cancer immunotherapy by eliciting type-I interferon (IFN-I) responses. Yet, current approaches to cGAS-STING activation rely on STING agonists, which suffer from difficult formulation, poor pharmacokinetics, and marginal clinical therapeutic eff...

Glioblastoma multiforme (GBM) is the most common and lethal type of adult brain cancer. Current GBM standard of care, including radiotherapy, often ends up with cancer recurrence, resulting in limited long-term survival benefits for GBM patients. Immunotherapy, such as immune checkpoint blockade (ICB), has thus far shown limited clinical benefit fo...

Current cancer immunotherapy [e.g., immune checkpoint blockade (ICB)] only benefits small subsets of patients, largely due to immunosuppressive tumor microenvironment (TME). In situ tumor vaccination can reduce TME immunosuppression and thereby improve cancer immunotherapy. Here, we present single-dose injectable (nanovaccines + ICBs)-in-hydrogel (...

Current cancer immunotherapy (e.g., immune checkpoint blockade (ICB)) has only benefited a small subset of patients. Cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) activation holds the potential to improve cancer immunotherapy by eliciting type-I interferon (IFN-I) responses in cancer cells and myeloid cells. Yet, current appro...

Rheumatoid arthritis (RA) is a systemic autoimmune disease with pathogenic inflammation caused partly by excessive cell‐free DNA (cfDNA). Specifically, cfDNA is internalized into immune cells, such as macrophages in lymphoid tissues and joints, and activates pattern recognition receptors, including cyclic guanosine monophosphate–adenosine monophosp...

Ionizable lipid nanocarriers have made historical contribution to COVID-19 mRNA vaccines. Here, we report ionizable polymeric nanoparticles that co-deliver bi-adjuvant and neoantigen peptides for cancer immunotherapy in combination with immune checkpoint blockade (ICB). Current cancer ICB benefits only a small subset of patients, largely due to a l...

Immune checkpoint blockade (ICB) has significantly advanced cancer immunotherapy, yet its patient response rates are generally low. Vaccines, including immunostimulant‐adjuvanted peptide antigens, can improve ICB. The emerging neoantigens generated by cancer somatic mutations elicit cancer‐specific immunity for personalized immunotherapy; the novel...

The past decade has witnessed the blossom of nucleic acid therapeutics and diagnostics (theranostics). Unlike conventional small molecule medicines or protein biologics, nucleic acid theranostics have characteristic features such as the intrinsic ability as "information drugs" to code and execute genetic and theranostic information, ready programma...

Cancer has been one of the major healthcare burdens, which demands innovative therapeutic strategies to improve the treatment outcomes. Combination therapy hold great potential to leverage multiple synergistic pathways to improve cancer treatment. Cancer cells often exhibit an increased generation of reactive oxygen species (ROS) and antioxidant sp...

Cancer immunotherapy has made recent breakthrough, including immune checkpoint blockade (ICB) that inhibits immunosuppressive checkpoints such as programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1). However, most cancer patients do not durably respond to ICB. To predict ICB responses for patient stratification, conventional...

Cyclic dinucleotides (CDNs), such as c‐di‐GMP (CDG), are agonists for stimulator of interferon genes (STING) and are promising for cancer immunotherapy. Yet, the therapeutic efficacy of CDNs has been limited by poor delivery and biostability. Here, STING‐activating DNA nanovaccines (STING‐NVs) are developed, which biostabilize, deliver, and conditi...

The past decade has witnessed the blossom of two fields: nucleic acid therapeutics and cancer immunotherapy. Unlike traditional small molecule medicines or protein biologics, nucleic acid therapeutics have characteristic features such as storing genetic information, immunomodulation, and easy conformational recovery. Immunotherapy uses the patients...

Neoantigen vaccines have been enthusiastically pursued for personalized cancer immunotherapy while vast majority of neoantigens have no or low immunogenicity. Here, a bi-adjuvant neoantigen nanovaccine (banNV) that codelivered a peptide neoantigen (Adpgk) with two adjuvants [Toll-like receptor (TLR) 7/8 agonist R848 and TLR9 agonist CpG] was develo...

Cancer immunotherapy modulates and leverages the host immune system to treat cancer. The past decade has witnessed historical advancement of cancer immunotherapy. A myriad of approaches have been explored to elicit or augment anticancer innate immunity and/or adaptive immunity. Recently, activation of stimulator of interferon (IFN) genes (STING), a...

Reactive oxygen species (ROS)-generating anticancer agents can act through two different mechanisms: (i) elevation of endogenous ROS production in mitochondria, or (ii) formation/delivery of exogenous ROS within cells. However, there is a lack of research on the development of ROS-generating nanosystems that combine endogenous and exogenous ROS to...

Metal-organic framework (MOF) nanoparticles have shown great potential as carrier platforms in theranostic applications. However, their poor physiological stability in phosphate-based media has limited their biological applications. Here, we studied the dissociation of MOF nanoparticles under physiological conditions, both in vitro and in vivo, and...

The past few decades have witnessed the booming field of cancer immunotherapy. Cancer therapeutic vaccines, either alone or in combination with other immunotherapies such as adoptive cell therapy or immune checkpoint blockade therapy, are an attractive class of cancer immunotherapeutics. However, cancer vaccines have thus far shown suboptimal effic...

The effectiveness of numerous molecular drugs is hampered by their poor pharmacokinetics. Different from previous approaches with limited effectiveness, most recently, emerging high-affinity albumin binding moieties (ABMs) for in vivo hitchhiking endogenous albumin opens up an avenue to chaperon small molecules for long-acting therapeutics. Althoug...

Nanomedicine has become a promising approach to improve cancer chemotherapy. It remains a major challenge how to enhance anti-drug efficacy and reduce side effects of anti-cancer drugs. Herein, we report a self-assembled nanoplatform (FDEP NPs) by integration of doxorubicin (DOX) and epigallocatechin-3-O-gallate (EGCG) with the help of coordination...

Objective: Epidermal growth factor receptor (EGFR) is a theranostic biomarker for a variety of cancer types. The aim of the present study was to develop an 18F radiolabeled EGFR targeting RNA aptamer, and to investigate its ability to visualize and quantify EGFR in xenograft models. Methods: Biolayer interferometry binding assay was used to dete...

Cancer vaccine is an important form of immunotherapy. Given their effectiveness for antigen processing and presentation, dendritic cells (DCs) have been exploited in the development of therapeutic vaccine. Herein, a versatile polymersomal nanoformulation that enables generation of tumor-associated antigens (TAAs) and simultaneously serves as adjuva...

During photodynamic therapy (PDT), severe hypoxia often occurs as an undesirable limitation of PDT owing to the O2‐consuming photodynamic process, compromising the effectiveness of PDT. To overcome this problem, several strategies aiming to improve tumor oxygenation are developed. Unlike these traditional approaches, an opposite method combining hy...

Type 1 diabetes mellitus (T1DM) is an autoimmune disease affecting 3 million individuals in the U.S. The pathogenesis of T1DM is driven by immune-mediated destruction of pancreatic β cells, the source of glucose regulator insulin. While T1DM can be successfully managed with insulin replacement therapy, approaches that can modify the underlying immu...

The original version of this article contained a mistake in the first paragraph of "Cell uptake and internalization of 18F-FB-ME07" section. The text "The specific activity was 7.4-14.8 kBq/nmol" should have been "The specific activity was 7.4-14.8 Mbq/nmol".

Cancer is one of the leading causes of morbidity and mortality in the world. But more cancer therapies are needed to complement existing regimens due to problems of existing cancer therapies. Herein, we term ferroptosis therapy (FT) as a form of cancer therapy, and hypothesize that the FT efficacy can be significantly improved via accelerating the...

Precision medicine holds great promise to harness genetic and epigenetic cues for targeted treatment of a variety of diseases, ranging from many types of cancers, neurodegenerative diseases, to cardiovascular diseases. The proteomic profiles resulting from the unique genetic and epigenetic signatures represent a class of relatively well accessible...

Polymeric micelle‐based drug delivery systems have dramatically improved the delivery of small molecular drugs, yet multiple challenges remain to be overcome. In this work, we engineered a polymeric nanomedicine that possesses an ultrahigh loading (59%) of a glutathione (GSH)‐sensitive heterodimeric multifunctional prodrug (HDMP) to effectively co‐...

Polymeric micelle‐based drug delivery systems have dramatically improved the delivery of small molecular drugs, yet multiple challenges remain to be overcome. In this work, we engineered a polymeric nanomedicine that possesses an ultrahigh loading (59%) of a glutathione (GSH)‐sensitive heterodimeric multifunctional prodrug (HDMP) to effectively co‐...

In situ rolling circle transcription (RCT) is applied by Qianqian Ni and co-workers to develop a “core–shell” microstructure. As described by Guizhi Zhu, Longjiang Zhang, Xiaoyuan Chen, and co-workers in article number 1705737, poly(short hairpin RNA) (shRNA) is synthesized on amphiphilic DNA–polylactide (PLA) nanoparticles for co-delivery of thera...

We herein describe a simple and versatile approach to use conventional nicking endonuclease (NEase) for programmable sequence-specific cleavage of DNA, termed aligner-mediated cleavage (AMC), and its application to DNA isothermal exponential amplification (AMC-based strand displacement amplification, AMC-SDA). AMC uses a hairpin-shaped DNA aligner...

Folate receptor (FR) has proven to be a valuable target for chemotherapy using folic acid (FA) conjugates. However, FA-conjugated chemotherapeutics still have low therapeutic efficacy accompanied with side effects, resulting from complications such as short circulation half-life, limited tumor delivery, as well as high kidney accumulation. Herein,...

Nanomedicine has shown unprecedented potential for cancer theranostics. Nucleic acid (e.g., DNA and RNA) nanomedicines are of particular interest for combination therapy with chemotherapeutics. However, current nanotechnologies to construct such nucleic acid nanomedicines, which rely on chemical conjugation or physical complexation of nucleic acids...

Engineering functional nanomaterials with high therapeutic efficacy and minimum side effects has increasingly become a promising strategy for cancer treatment. Herein, a reactive oxygen species (ROS) enhanced combination chemotherapy platform is designed via a biocompatible metal-polyphenol networks self-assembly process by encapsulating doxorubici...

Purpose: Radionuclide therapy directed against tumors that express somatostatin receptors (SSTRs) has proven effective for the treatment of advanced, low- to intermediate-grade neuroendocrine tumors in the clinic. In clinical usage, somatostatin peptide-based analogs, labeled with therapeutic radionuclides, provide an overall response rate of about...

Radiolabeled bombesin (BBN) analogs have long been used for developing gastrin-releasing peptide receptor (GRPR) targeted imaging probes, and tracers with excellent in vivo performance including high tumor uptake, high contrast, and favorable pharmacokinetics are highly desired. In this study, we compared 68Ga-labeled GRPR agonist (Gln-Trp-Ala-Val-...

Subunit vaccines have been investigated in over 1000 clinical trials of cancer immunotherapy, but have shown limited efficacy. Nanovaccines may improve efficacy but have rarely been clinically translated. By conjugating molecular vaccines with Evans blue (EB) into albumin-binding vaccines (AlbiVax), here we develop clinically promising albumin/Albi...

Nanomedicines that co-deliver DNA, RNA, and peptide therapeutics are highly desirable yet remain underdeveloped for cancer theranostics. Herein, we report self-assembled intertwining DNA-RNA nanocapsules (iDR-NCs) that efficiently delivered synergistic DNA CpG and short hairpin RNA (shRNA) adjuvants, as well as tumor-specific peptide neoantigens in...

The recently emerged exceedingly small magnetic iron oxide nanoparticles (ES-MIONs) (< 5 nm) are promising T1-weighted contrast agents for magnetic resonance imaging (MRI) due to their good biocompatibility compared with Gd-chelates. However, the best particle size of ES-MIONs for T1 imaging is still unknown because the synthesis of ES-MIONs with p...

Polyphosphoester-based nanoparticles are capable of loading paclitaxel chemically and physically, achieving ultrahigh equivalent paclitaxel aqueous concentrations.

The clearance of nanoparticles (NPs) by mononuclear phagocyte system (MPS) from blood leads to high liver and spleen uptake and negatively impacts their tumor delivery efficiency. Here we systematically evaluated the in vitro and in vivo nano-bio interactions of a two-dimensional (2D) model, gold (Au) nanorings, which were compared with Au nanosphe...

Highly efficient antimicrobial agents with low toxicity and resistance have been enthusiastically pursued to address public concerns on microbial contamination in food. Silver nanoclusters (AgNCs) are known for their ultra-small sizes and unique optical and chemical properties. Despite extensive studies of AgNCs for biomedical applications, previou...

We report a camptothecin (CPT) prodrug that was well formulated in solution and rapidly transformed into long-circulating nanocomplexes in vivo for highly efficient drug delivery and effective cancer therapy. Specifically, using a redox-responsive disulfide linker, CPT was conjugated with an albumin-binding Evans Blue (EB) derivative; the resulting...

Janus nanoparticles enable excellent applications that are unavailable to their symmetrical counterparts. Assemblies of NPs exhibit coupled optical, electronic and magnetic properties that are different from single NPs. Herein, we report a new class of double-layered plasmonic-magnetic vesicle assembled from Janus amphiphilic Au-Fe3O4 NPs grafted w...

Janus nanoparticles (JNPs) offer unique features, including the precisely controlled distribution of compositions, surface charges, dipole moments, modular and combined functionalities, which enable excellent applications that are unavailable to their symmetrical counterparts. Assemblies of NPs exhibit coupled optical, electronic and magnetic prope...

Advances in nanoparticle synthesis and engineering have produced nanoscale agents affording both therapeutic and diagnostic functions that are often referred to by the portmanteau ‘nanotheranostics’. The field is associated with many applications in the clinic, especially in cancer management. These include patient stratification, drug-release moni...

Vaccines hold tremendous potential for cancer immunotherapy by treating the immune system. Subunit vaccines, including molecular adjuvants and cancer-associated antigens or cancer-specific neoantigens, can elicit potent antitumor immunity. However, subunit vaccines have shown limited clinical benefit in cancer patients, which is in part attributed...

Evading the reticuloendothelial system (RES) remains a critical challenge in the development of efficient delivery and diagnostic systems for cancer. Sialic acid (N-acetylneuraminic acid, Neu5Ac) is recognized as a “self” marker by major serum protein complement factor H and shows reduced interaction with the innate immune system via sialic acid-bi...

Supplementary figures and tables.

HER2, a cell membrane protein overexpressed in many types of cancers, is correlated with poor diagnosis, suboptimal treatment outcome, and low survival rate. Multiple HER2-targeted drugs have been developed for the treatment of HER2-overexpressing tumor, which can in turn down-regulate HER2 expression. It is thus significant to profile HER2 express...

Purpose: Sentinel lymph node biopsy (SLNB) has emerged as the preferred standard procedure in patients with breast cancer, melanoma and other types of cancer. Herein, we developed a method to intra-operatively map SLNs and differentiate tumor metastases within SLNs at the same time, with the aim to provide more accurate and real-time intraoperative...

Supplementary figures.

The development of biocompatible drug delivery systems with targeted recognition and controlled release has experienced a number of design challenges, including, for example, complicated preparation steps and premature drug release. Herein, we address these problems through an in situ self-polymerization method that synthesizes biodegradable polyph...

Cancer evolves to evade or compromise the surveillance of immune system, and cancer immunotherapy aims to harness the immune system in order to inhibit cancer development. Unmethylated CpG dinucleotide-containing oligonucleotides (CpG), a class of potent adjuvants that activate the Toll-like Receptor 9 (TLR9) located in the endolysosome of many ant...

AS1411 (previously known as AGRO100) is a 26 nucleotide guanine-rich DNA aptamer which forms a guanine quadruplex structure. AS1411 has shown promising utility as a treatment for cancers in Phase I and Phase II clinical trials without causing major side-effects. AS1411 inhibits tumor cell growth by binding to nucleolin which is aberrantly expressed...

Synthetic unmethylated cytosine-guanine (CpG) oligodeoxynucleotides (ODNs) are immunostimulatory motifs that have shown promise as vaccines or adjuvants for diseases such as cancers and infectious diseases. In the present work, novel immuno-nanoflowers (NFs), self-assembled from long DNA integrated with tandem CpG through rolling circle replication...

On-demand release of carbon monoxide (CO) is realized through a novel near-infrared-responsive nanomedicine in favor of the enhancement of therapy efficacy and biosafety of CO therapy.

Cancer chemotherapy has been limited by its side effects and multidrug resistance (MDR), the latter of which is partially caused by drug efflux from cancer cells. Thus, targeted drug delivery systems that can circumvent MDR are needed. Here, we report multifunctional DNA nanoflowers (NFs) for targeted drug delivery to both chemosensitive and MDR ca...

We describe a comprehensive protocol for the preparation of multifunctional DNA nanostructures termed nanoflowers (NFs), which are self-assembled from long DNA building blocks generated via rolling-circle replication (RCR) of a designed template. NF assembly is driven by liquid crystallization and dense packaging of building blocks, which eliminate...

Methods: Sgc8, a 41-oligonucleotide that targets to PTK7, was labeled with F-18 using a two-step radiochemical synthesis, which featured a direct one-step radiofluorination on the distinctive spirocyclic hypervalent iodine(III) precursor to give (18)F-fluorobenzyl azide followed by copper mediated "click" conjugation with Sgc8-alkyne. (18)F-Sgc8 w...

A DNAzyme-based ELISA, termed DLISA, was developed as a novel protein enzyme-free, triply-amplified platform, combining a catalytic and molecular beacon (CAMB) system with a cation exchange reaction for ultrasensitive multiplex fluorescent immunosorbent assay. Classical ELISA, which employs protein enzymes as biocatalysts to afford amplified signal...

Western medicine often aims to specifically treat diseased tissues or organs. However, the majority of current therapeutics failed to do so owing to their limited selectivity and the consequent "off-target" side effects. Targeted therapy aims to enhance the selectivity of therapeutic effects and reduce adverse side effects. One approach towards thi...

Axiomatically, the density of information stored in DNA, with just four nucleotides (GACT), is higher than in a binary code, but less than it might be if synthetic biologists succeed in adding independently replicating nucleotides to genetic systems. Such addition could also add additional functional groups, not found in natural DNA but useful for...

The past two decades have witnessed the booming of DNA aptamers, and particularly the development of aptamers for the specific recognition of versatile disease-related molecular biomarkers and living cells, as well as the application of aptamers for molecular and cellular engineering, bioanalysis, and disease therapy. Owing to the predictable Watso...

Targeted drug delivery is poised to improve cancer therapy, for which synthetic DNA can serve as targeting ligands (for example, aptamers) or drug nanocarriers. Inspired by natural DNA adducts, we report synthetic drug-DNA adducts (DDAs) for targeted anticancer drug delivery. Multiple copies of anthracycline drugs were site specifically (on deoxygu...

The application of cancer theranostics depends on the development of multifunctional nanostructured platforms for accurate cell targeting and controlled drug release, imaging, and therapy. Herein, a comprehensive, easily fabricated anticancer theranostic platform with a high drug-loading capacity, termed an aptamer-functionalized calcium carbonate...

The development of multidrug resistance (MDR) has become an increasingly serious problem in cancer therapy. The cell-membrane overexpression of P-glycoprotein (P-gp), which can actively efflux various anticancer drugs from the cell, is a major mechanism of MDR. Nuclear-uptake nanodrug delivery systems, which enable intranuclear release of anticance...

The specific inventory of molecules on diseased cell surfaces (e.g., cancer cells) provides clinicians an opportunity for accurate diagnosis and intervention. With the discovery of panels of cancer markers, carrying out analyses of multiple cell-surface markers is conceivable. As a trial to accomplish this, we have recently designed a DNA-based dev...

Cell membrane-anchored biochemical sensors that allow real-time monitoring of the interactions of cells with their microenvironment would be powerful tools for studying the mechanisms underlying various biological processes, such as cell metabolism and cell signaling. Despite the significance of these techniques, unfortunately, their development ha...

Nonpolar phase synthesized hydrophobic nanocrystals show attractive properties and have demonstrated prominent potential in biomedical applications. However, the preparation of biocompatible nanocrystals is made difficult by the presence of hydrophobic surfactant stabilizer on their surfaces. To address this limitation, we have developed a facile,...

A novel nanohybrid of hyaluronic acid (HA)-decorated graphene oxide(GO) was fabricated as targeted and pH-response drug delivery system for controlling release anticancer drug doxorubicin (DOX) for tumor therapy. For the preparation, DOX was first loaded onto GO nanocarriers via π-π stacking and hydrogen bonding interactions, and then decorated wit...

We present a facile approach to make aptamer-conjugated FRET (fluorescent resonance energy transfer) nanoflowers (NFs) through rolling circle replication for multiplexed cellular imaging and traceable targeted drug delivery. The NFs can exhibit multi-fluorescence emissions by a single-wavelength excitation as a result of the DNA matrix covalently i...

We present a facile approach to make aptamer-conjugated FRET (fluorescent resonance energy transfer) nanoflowers (NFs) through rolling circle replication for multiplexed cellular imaging and traceable targeted drug delivery. The NFs can exhibit multi-fluorescence emissions by a single-wavelength excitation as a result of the DNA matrix covalently i...

Functional nucleic acids (FNAs)-based sensing systems have been developed for efficient detection of a wide range of biorelated analytes by employing DNAzymes or aptamers as recognition units. However, their intracellular delivery has always been a concern, mainly in delivery efficiency, kinetics and the amount of delivered FNAs. Here we report a D...

The development of nanomaterials that combine diagnostic and therapeutic functions within a single nanoplatform is extremely important for molecular medicine. Molecular imaging with simultaneous diagnosis and therapy will provide the multimodality needed for accurate diagnosis and targeted therapy. Here, gold-coated iron oxide (Fe3O4@Au) nanoroses...

Aptamer-drug conjugates (ApDCs) are promising targeted drug delivery systems for reducing toxicity while increasing the efficacy of chemotherapy. However, current ApDC tech-nologies suffer from problems caused by the complicated preparation and low controllability of drug-aptamer conjugation. To solve such problems, we have designed and synthesized...

Background: Aptamer-drug conjugates are promising to be applied to targeted cancer therapy, in which anticancer drugs were selectively delivered into cognate cancerous cells, but not to healthy tissues, in order to reduce side effects and enhance therapeutic efficacy. Methodology/Principal Findings: In this study, the technology of drug-DNA adduct...

A therapeutic aptamer–lipid–poly(lactide-co-glycolic acid) hybrid nanoparticle-based drug delivery system was prepared and characterized. This system can co-deliver two different drugs with distinct solubility and different anticancer mechanisms to target cancer cells with high specificity and efficiency.

Significance Many chemicals are valuable because they bind to other molecules. Chemical theory cannot directly design “binders.” However, we might recreate in the laboratory the Darwinian processes that nature uses to create binders. This in vitro evolution uses nucleic acids as binders, libraries of DNA/RNA to survive a selection challenge before...