Dendrimer Platforms for Targeted Doxorubicin Delivery-Physicochemical Properties in Context of Biological Responses.

The unique structure of G4.0 PAMAM dendrimers allows a drug to be enclosed in internal spaces or immobilized on the surface. In the conducted research, the conditions for the formation of the active G4.0 PAMAM complex with doxorubicin hydrochloride (DOX) were optimized. The physicochemical properties of the system were monitored using dynamic light scattering (DLS), circular dichroism (CD), and fluorescence spectroscopy. The Quartz Crystal Microbalance with Dissipation Monitoring (QCM-D) method was chosen to determine the preferential conditions for the complex formation. The highest binding efficiency of the drug to the cationic dendrimer was observed under basic conditions when the DOX molecule was deprotonated. The decrease in the zeta potential of the complex confirms that DOX immobilizes through electrostatic interaction with the carrier's surface amine groups. The binding constants were determined from the fluorescence quenching of the DOX molecule in the presence of G4.0 PAMAM. The two-fold way of binding doxorubicin in the structure of dendrimers was visible in the Isothermal calorimetry (ITC) isotherm. Fluorescence spectra and release curves identified the reversible binding of DOX to the nanocarrier. Among the selected cancer cells, the most promising anticancer activity of the G4.0-DOX complex was observed in A375 malignant melanoma cells. Moreover, the preferred intracellular location of the complexes concerning the free drug was found, which is essential from a therapeutic point of view.

PAMAM dendrimers as mediators of dermal and transdermal drug delivery: a review.

OBJECTIVES: Poly(amidoamine) dendrimers have been widely investigated as potential nanomaterials that can enhance the skin permeation of topically applied drugs. This article reviews the studies that have used dendrimers as penetration enhancers and examines the mechanisms by which enhancement is claimed. KEY FINDINGS: A wide range of studies have demonstrated that, in certain circumstances and for certain drugs, the incorporation of dendrimers into a topically applied formulation can significantly increase the amount of drug passing into and through the skin. In some cases, dendrimers offered little or no enhancement of skin permeation, suggesting that the drug-dendrimer interaction and the selection of a specific dendrimer were central to ensuring optimal enhancement of skin permeation. Significant interactions between dendrimers and other formulation components were also reported in some cases. SUMMARY: Dendrimers offer substantial potential for enhancing drug delivery into and across the skin, putatively by mechanisms that include occlusion and changes to surface tension. However, most of these studies are conducted in vitro and limited progress has been made beyond such laboratory studies, some of which are conducted using membranes of limited relevance to humans, such as rodent skin. Thus, the outcomes and claims of such studies should be treated with caution.

The Hamilton Receptor in Supramolecular Polymer Sciences.

Supramolecular polymers are polymeric materials of monomeric fragments, held jointly by reversible and directional non-covalent interactions such as multiple hydrogen-bonding, charge transfer effects, host-guest interactions, metal coordination, and aromatic stacking. This review article on the Hamilton-based supramolecular polymers aims to shed light on the molecular recognition achievements by the Hamilton-based polymeric systems, evaluate Hamilton receptor's future prospects, and capitalize its potential applications in supramolecular chemistry. To the best of our knowledge, this is the first elaborative and sole manuscript in which polymeric Hamilton receptors are being exposed in detail. The first portion of this manuscript is related to the importance and urgency of polymers along with the historic background of Hamilton receptors. The middle section discloses the potential applications of Hamilton-type receptors in various fields, e.g., dendrimers, mechanically polymeric rotaxanes, and self-assemblies. The final section of the manuscript discloses the future aspects and the importance of novel polymer-based Hamilton-type receptors in the modern era. We believe that this first review in this emerging yet immature field will be useful to inspire scientists around the world to find the unseen future prospects, thereby boosting the field related to this valued artificial receptor in the province of supramolecular chemistry and also in other domains of scientific fields and technology, as well.

Advancements in Nanoparticle-Based Strategies for Enhanced Antibacterial Interventions.

The escalating global threat of antibiotic resistance underscores the urgent need for innovative antimicrobial strategies. This review explores the cutting-edge applications of nanotechnology in combating bacterial infections, addressing a critical healthcare challenge. We critically assess the antimicrobial properties and mechanisms of diverse nanoparticle systems, including liposomes, polymeric micelles, solid lipid nanoparticles, dendrimers, zinc oxide, silver, and gold nanoparticles, as well as nanoencapsulated essential oils. These nanomaterials offer distinct advantages, such as enhanced drug delivery, improved bioavailability, and efficacy against antibiotic-resistant strains. Recent advancements in nanoparticle synthesis, functionalization, and their synergistic interactions with conventional antibiotics are highlighted. The review emphasizes biocompatibility considerations, stressing the need for rigorous safety assessments in nanomaterial applications. By synthesizing current knowledge and identifying emerging trends, this review provides crucial insights for researchers and clinicians aiming to leverage nanotechnology for next-generation antimicrobial therapies. The integration of nanotechnology represents a promising frontier in combating infectious diseases, underscoring the timeliness and imperative of this comprehensive analysis.

1,3,5-Triazine as Branching Connector for the Construction of Novel Antimicrobial Peptide Dendrimers: Synthesis and Biological Characterization.

Peptides displaying antimicrobial properties are being regarded as useful tools to evade and combat antimicrobial resistance, a major public health challenge. Here we have addressed dendrimers, attractive molecules in pharmaceutical innovation and development displaying broad biological activity. Triazine-based dendrimers were fully synthesized in the solid phase, and their antimicrobial activity and some insights into their mechanisms of action were explored. Triazine is present in a large number of compounds with highly diverse biological targets with broad biological activities and could be an excellent branching unit to accommodate peptides. Our results show that the novel peptide dendrimers synthesized have remarkable antimicrobial activity against Gram-negative bacteria (E. coli and P. aeruginosa) and suggest that they may be useful in neutralizing the effect of efflux machinery on resistance.

Targetable domains for the design of peptide-dendrimer inhibitors of SARS-CoV-2.

We have recently witnessed that considerable progresses have been made in the rapid detection and appropriate treatments of COVID-19, but still this virus remains one of the main targets of world research. Based on the knowledge of the complex mechanism of viral infection we designed peptide-dendrimer inhibitors of SARS-CoV-2with the aim to block cell infection through interfering with the host-pathogen interactions. We used two different strategies: i) the first one aims at hindering the virus anchorage to the human cell; ii) the second -strategy points to interfere with the mechanism of virus-cell membrane fusion. We propose the use of different nanosized carriers, formed by several carbosilane dendritic wedges to deliver two different peptides designed to inhibit host interaction or virus entry. The antiviral activity of the peptide-dendrimers, as well as of free peptides and free dendrimers was evaluated through the use of SARS-CoV-2 pseudotyped lentivirus. The results obtained show that peptides designed to block host-pathogen interaction represent a valuable strategy for viral inhibition.

Homo and Hetero-Branched Lipopeptide Dendrimers: Synthesis and Antimicrobial Activity.

Di-branched and tetra-branched versions of a previously reported analogue of the lipopeptide battacin were successfully synthesised using thiol-maleimide click and 1, 2, 3-triazole click chemistry. Antimicrobial studies against drug resistant clinical isolates of Escherichia coli (ESBL E. coli Ctx-M14), Pseudomonas aeruginosa (P. aeruginosa Q502), and Methicillin resistant Staphylococcus aureus (MRSA ATCC 33593), as well as clinically isolated Acinetobacter baumannii (A. baumannii ATCC 19606), and P. aeruginosa (ATCC 27853), revealed that the dendrimeric peptides have antimicrobial activity in the low micromolar range (0.5 -- 4 µM) which was 10 times more potent than the monomer peptides. Under high salt concentrations (150 mM NaCl, 2 mM MgCl2, and 2.5 mM CaCl2) the di-branched lipopeptides retained their antimicrobial activity while the monomer peptides were not active (>100 µM). The di-branched triazole click lipopeptide, Peptide 12, was membrane lytic, showed faster killing kinetics, and exhibited antibiofilm activity against A. baumannii and MRSA and eradicated > 85 % preformed biofilms at low micromolar concentrations. The di-branched analogues were > 30-fold potent than the monomers against Candida albicans. Peptide 12 was not haemolytic (HC10 = 932.12 µM) and showed up to 40-fold higher selectivity against bacteria and fungi than the monomer peptide. Peptide 12 exhibited strong proteolytic stability (>80 % not degraded) in rat serum over 24 h whereas > 95 % of the thiol-maleimide analogue (Peptide 10) was degraded. The tetra-branched peptides showed comparable antibacterial potency to the di-branched analogues. These findings indicate that dual branching using triazole click chemistry is a promising strategy to improve the antimicrobial activity and proteolytic stability of battacin based lipopeptides. The information gathered can be used to build effective antimicrobial dendrimeric peptides as new peptide antibiotics.

In Silico Screening Accelerates Nanocarrier Design for Efficient mRNA Delivery.

Lipidic nanocarriers are a broad class of lipid-based vectors with proven potential for packaging and delivering emerging nucleic acid therapeutics. An important early step in the clinical development cycle is large-scale screening of diverse formulation libraries to assess particle quality and payload delivery efficiency. Due to the size of the screening space, this process can be both costly and time-consuming. To address this, computational models capable of predicting clinically relevant physio-chemical properties of dendrimer-lipid nanocarriers, along with their mRNA payload delivery efficiency in human cells are developed. The models are then deployed on a large theoretical nanocarrier pool consisting of over 4.5 million formulations. Top predictions are synthesised for validation using cell-based assays, leading to the discovery of a high quality, high performing, candidate. The methods reported here enable rapid, high-throughput, in silico pre-screening for high-quality candidates, and have great potential to reduce the cost and time required to bring mRNA therapies to the clinic.

Anti-biofilm, drug delivery and cytotoxicity properties of dendrimers.

Background and purpose: Treatments using antimicrobial agents have faced many difficulties as a result of biofilm formation by pathogenic microorganisms. The biofilm matrix formed by these microorganisms prevents antimicrobial agents from penetrating the interior where they can exact their activity effectively. Additionally, extracellular polymeric molecules associated with biofilm surfaces can absorb antimicrobial compounds, lowering their bioavailability. This problem has resulted in the quest for alternative treatment protocols, and the development of nanomaterials and devices through nanotechnology has recently been on the rise. Research approach: The literature on dendrimers was searched for in databases such as Google Scholar, PubMed, and ScienceDirect. Key results: As a nanomaterial, dendrimers have found useful applications as a drug delivery vehicle for antimicrobial agents against biofilm-mediated infections to circumvent these defense mechanisms. The distinctive properties of dendrimers, such as multi-valency, biocompatibility, high water solubility, non-immunogenicity, and biofilm matrix-/cell membrane fusogenicity (ability to merge with intracellular membrane or other proteins), significantly increase the efficacy of antimicrobial agents and reduce the likelihood of recurring infections. Conclusion: This review outlines the current state of dendrimer carriers for biofilm treatments, provides examples of their real-world uses, and examines potential drawbacks.

Radiation nanomedicines for cancer treatment: a scientific journey and view of the landscape.

BACKGROUND: Radiation nanomedicines are nanoparticles labeled with radionuclides that emit α- or ß-particles or Auger electrons for cancer treatment. We describe here our 15 years scientific journey studying locally-administered radiation nanomedicines for cancer treatment. We further present a view of the radiation nanomedicine landscape by reviewing research reported by other groups. MAIN BODY: Gold nanoparticles were studied initially for radiosensitization of breast cancer to X-radiation therapy. These nanoparticles were labeled with 111In to assess their biodistribution after intratumoural vs. intravenous injection. Intravenous injection was limited by high liver and spleen uptake and low tumour uptake, while intratumoural injection provided high tumour uptake but low normal tissue uptake. Further, [111In]In-labeled gold nanoparticles modified with trastuzumab and injected iintratumourally exhibited strong tumour growth inhibition in mice with subcutaneous HER2-positive human breast cancer xenografts. In subsequent studies, strong tumour growth inhibition in mice was achieved without normal tissue toxicity in mice with human breast cancer xenografts injected intratumourally with gold nanoparticles labeled with ß-particle emitting 177Lu and modified with panitumumab or trastuzumab to specifically bind EGFR or HER2, respectively. A nanoparticle depot (nanodepot) was designed to incorporate and deliver radiolabeled gold nanoparticles to tumours using brachytherapy needle insertion techniques. Treatment of mice with s.c. 4T1 murine mammary carcinoma tumours with a nanodepot incorporating [90Y]Y-labeled gold nanoparticles inserted into one tumour arrested tumour growth and caused an abscopal growth-inhibitory effect on a distant second tumour. Convection-enhanced delivery of [177Lu]Lu-AuNPs to orthotopic human glioblastoma multiforme (GBM) tumours in mice arrested tumour growth without normal tissue toxicity. Other groups have explored radiation nanomedicines for cancer treatment in preclinical animal tumour xenograft models using gold nanoparticles, liposomes, block copolymer micelles, dendrimers, carbon nanotubes, cellulose nanocrystals or iron oxide nanoparticles. These nanoparticles were labeled with radionuclides emitting Auger electrons (111In, 99mTc, 125I, 103Pd, 193mPt, 195mPt), ß-particles (177Lu, 186Re, 188Re, 90Y, 198Au, 131I) or α-particles (225Ac, 213Bi, 212Pb, 211At, 223Ra). These studies employed intravenous or intratumoural injection or convection enhanced delivery. Local administration of these radiation nanomedicines was most effective and minimized normal tissue toxicity. CONCLUSIONS: Radiation nanomedicines have shown great promise for treating cancer in preclinical studies. Local intratumoural administration avoids sequestration by the liver and spleen and is most effective for treating tumours, while minimizing normal tissue toxicity.

Adaptable Self-Assembly of a PEG Dendrimer-Coiled Coil Conjugate.

Self-assembly of designed molecules has enabled the construction of a variety of functional nanostructures. Specifically, adaptable self-assembly has demonstrated several advantageous features for smart materials. Here, we demonstrate that an α-helical coiled coil conjugated with a dendrimer can adapt to spatial restriction due to the strong steric repulsion between dendrimer chains. The adaptable transformation of a tetrameric coiled coil to a trimeric coiled coil can be confirmed using analytical ultracentrifugation upon conjugation of the dendrimer to the coiled coil-forming building block. Interestingly, circular dichroism spectroscopy analysis of the dendrimer conjugate revealed an unconventional trend: the multimerization of the coiled coil is inversely dependent on concentration. This result implies that the spatial crowding between the bulky dendritic chains is significantly stronger than that between linear chains, thereby affecting the overall assembly process. We further illustrated the application potential by decorating the surface of gold nanorods (AuNRs) with the adaptable coiled coil. The dendrimer-coiled coil peptide conjugate can be utilized to fabricate organic-inorganic nanohybrids with enhanced colloidal and thermal stabilities. This study demonstrates that the coiled coil can engage in the adaptable mode of self-assembly with the potential to form dynamic peptide-based materials.

Selective targeting and modulation of plaque associated microglia via systemic hydroxyl dendrimer administration in an Alzheimer's disease mouse model.

BACKGROUND: In Alzheimer's disease (AD), microglia surround extracellular plaques and mount a sustained inflammatory response, contributing to the pathogenesis of the disease. Identifying approaches to specifically target plaque-associated microglia (PAMs) without interfering in the homeostatic functions of non-plaque associated microglia would afford a powerful tool and potential therapeutic avenue. METHODS: Here, we demonstrated that a systemically administered nanomedicine, hydroxyl dendrimers (HDs), can cross the blood brain barrier and are preferentially taken up by PAMs in a mouse model of AD. As proof of principle, to demonstrate biological effects in PAM function, we treated the 5xFAD mouse model of amyloidosis for 4 weeks via systemic administration (ip, 2x weekly) of HDs conjugated to a colony stimulating factor-1 receptor (CSF1R) inhibitor (D-45113). RESULTS: Treatment resulted in significant reductions in amyloid-beta (Aß) and a stark reduction in the number of microglia and microglia-plaque association in the subiculum and somatosensory cortex, as well as a downregulation in microglial, inflammatory, and synaptic gene expression compared to vehicle treated 5xFAD mice. CONCLUSIONS: This study demonstrates that systemic administration of a dendranib may be utilized to target and modulate PAMs.

Self-Immolative Domino Dendrimers as Anticancer-Drug Delivery Systems: A Review.

Worldwide cancer statistics have indicated about 20 million new cancer cases and over 10 million deaths in 2022 (according to data from the International Agency for Research on Cancer). One of the leading cancer treatment strategies is chemotherapy, using innovative drug delivery systems (DDSs). Self-immolative domino dendrimers (SIDendr) for triggered anti-cancer drugs appear to be a promising type of DDSs. The present review provides an up-to-date survey on the contemporary advancements in the field of SIDendr-based anti-cancer drug delivery systems (SIDendr-ac-DDSs) through an exhaustive analysis of the discovery and application of these materials in improving the pharmacological effectiveness of both novel and old drugs. In addition, this article discusses the designing, chemical structure, and targeting techniques, as well as the properties, of several SIDendr-based DDSs. Approaches for this type of targeted DDSs for anti-cancer drug release under a range of stimuli are also explored.

Organic Nanoparticles in Progressing Cardiovascular Disease Treatment and Diagnosis.

Cardiovascular diseases (CVDs), the world's most prominent cause of mortality, continue to be challenging conditions for patients, physicians, and researchers alike. CVDs comprise a wide range of illnesses affecting the heart, blood vessels, and the blood that flows through and between them. Advances in nanomedicine, a discipline focused on improving patient outcomes through revolutionary treatments, imaging agents, and ex vivo diagnostics, have created enthusiasm for overcoming limitations in CVDs' therapeutic and diagnostic landscapes. Nanomedicine can be involved in clinical purposes for CVD through the augmentation of cardiac or heart-related biomaterials, which can be functionally, mechanically, immunologically, and electrically improved by incorporating nanomaterials; vasculature applications, which involve systemically injected nanotherapeutics and imaging nanodiagnostics, nano-enabled biomaterials, or tissue-nanoengineered solutions; and enhancement of sensitivity and/or specificity of ex vivo diagnostic devices for patient samples. Therefore, this review discusses the latest studies based on applying organic nanoparticles in cardiovascular illness, including drug-conjugated polymers, lipid nanoparticles, and micelles. Following the revised information, it can be concluded that organic nanoparticles may be the most appropriate type of treatment for cardiovascular diseases due to their biocompatibility and capacity to integrate various drugs.

Silver Dendritic Gels with Luminescence and Aggregation-Induced Emission Effect.

This work reports on a novel family of silver metallogels based on discrete coordination complexes. Structurally, they consist of dendrimers containing a trinuclear silver metallacycle at the core, with the general formula [M(µ-pz)]3, and poly(benzyl)ether branched structures with different numbers or terminal alkoxy chains at the periphery. These silver metallodendrimers are able to gel low-polarity solvents such as dodecane or cyclohexane, giving rise to luminescent organogels at room temperature with the property of aggregation-induced emission (AIE). This property means that in solution or the sol state, they are weak emitters, but in the gel state, luminescence is considerably increased. In this particular case, they exhibit blue luminescence. Two different dendritic scaffolds have been studied, finding significant differences in solubility, gel formation and dependence of luminescence on temperature. The results show that properly tailored silver gelators can show luminescence in the gel state.

Polyphenolic dendrimers as carriers of anticancer siRNA.

Dendrimers have emerged as an important group of nanoparticles to transport drugs, DNA, or RNA into target cells in cancer and other diseases. Various functional modifications can be imposed on dendrimers to increase the efficacy and specificity in delivering their cargo to the target cells and decrease their toxicity. In the present work, we evaluated the potential of carbosilane polyphenolic dendrimers modified with caffeic acid (CA) and polyethylene glycol (PEG) to deliver proapoptotic Mcl-1 and Bcl-2 siRNAs to A549 cancer cells. Dendrimers formed stable complexes with siRNAs as assessed by transmission electron microscopy and gel electrophoresis. Modification of dendrimers with PEG reduced the size and the zeta potential of dendrimer/siRNA complexes. The presence of PEG caused a red shift of the CD spectrum, and this effect was the more pronounced, the higher the dendrimer/siRNA ratio was. The nanocomplexes were internalized by A549. All studied dendrimer/siRNA formulations inhibited tumor cell migration and adhesion and caused an increase in the population of early apoptotic cells. Among four tested dendrimers, the polyphenolic compound containing two caffeic acid moieties complexed with siRNA demonstrated the lowest polydispersity index and showed an excellent transfection profile. In conclusion, this dendrimer are a promising candidate for the delivery of siRNA into cancer cells in further in vivo studies.

Nanotechnology Integrated Innovative Drug Delivery and Therapy for Cancer.

Cancer remains a significant global health challenge, necessitating innovative approaches to enhance the efficacy and specificity of therapeutic interventions while minimizing adverse effects on healthy tissues. Nanotechnology has emerged as a promising avenue in cancer treatment, offering novel strategies for targeted drug delivery. Nanoparticles, liposomes, and polymer-based systems have played pivotal roles in revolutionizing cancer therapy. Nanotechnology possesses unique physicochemical properties, enabling efficient encapsulation of therapeutic agents and controlled and prolonged release at tumour sites. Advancement in formulations using nanotechnology has made it possible to make multifunctional systems that respond to the microenvironment of a tumour by releasing payloads in response to changes in pH, temperature, or enzymes. Stimuli-responsive polymers can release drugs in response to external cues, enabling site-specific drug release and minimizing systemic exposure. This review explores recent studies and preclinical trials that show how nanoparticles, liposomes, and polymerbased systems could be used to treat cancer, discussing challenges such as scalability, regulatory approval, and potential toxicity concerns along with patents published recently.

Brain delivery of fibronectin through bioactive phosphorous dendrimers for Parkinson's disease treatment via cooperative modulation of microglia.

Effective treatment of Parkinson's disease (PD), a prevalent central neurodegenerative disorder particularly affecting the elderly population, still remains a huge challenge. We present here a novel nanomedicine formulation based on bioactive hydroxyl-terminated phosphorous dendrimers (termed as AK123) complexed with fibronectin (FN) with anti-inflammatory and antioxidative activities. The created optimized AK123/FN nanocomplexes (NCs) with a size of 223 nm display good colloidal stability in aqueous solution and can be specifically taken up by microglia through FN-mediated targeting. We show that the AK123/FN NCs are able to consume excessive reactive oxygen species, promote microglia M2 polarization and inhibit the nuclear factor-kappa B signaling pathway to downregulate inflammatory factors. With the abundant dendrimer surface hydroxyl terminal groups, the developed NCs are able to cross blood-brain barrier (BBB) to exert targeted therapy of a PD mouse model through the AK123-mediated anti-inflammation for M2 polarization of microglia and FN-mediated antioxidant and anti-inflammatory effects, thus reducing the aggregation of α-synuclein and restoring the contents of dopamine and tyrosine hydroxylase to normal levels in vivo. The developed dendrimer/FN NCs combine the advantages of BBB-crossing hydroxyl-terminated bioactive per se phosphorus dendrimers and FN, which is expected to be extended for the treatment of different neurodegenerative diseases.

Supramolecular assembly of dendronized diacetylenes into thermoresponsive chiral fibers and their covalent fixation through topochemical polymerization.

By combination of dendritic topological structures with photopolymerizable diacetylene, here we report on supramolecular chiral assembly of the dendronized diacetylenes in water. These dendronized diacetylenes are constituted with three-fold dendritic oligoethylene glycols (OEGs), bridged with a dipeptide from phenylalanine and glycine. These dendronized amphiphiles exhibit intensive propensity to aggregate in water and form helical fibers, which show characteristic thermoresponsive behavior with phase transition temperatures dominated by hydrophilicity of the dendritic OEGs. Topochemical polymerization of these supramolecular fibers through UV irradiation transfers them into the covalent helical dendronized polydiacetylenes. Chirality of these dendronized polydiacetylenes can be mediated through the thermally-induced phase transitions, but is also intriguingly dependent on vortex via stirring. Through stirring the solutions, chiralities of the dendronized polydiacetylenes are inverted, which can be reversibly recovered after keeping still the solution. Hydrogels are formed from these dendronized diacetylenes through concentration-enhanced interactions between the supramolecular fibers. Their mechanical properties can be greatly increased through thermally-enhanced interactions between the fibers with storage moduli increased from 20 Pa to a few hundred Pa. In addition, through photo-polymerization, the supramolecular fibers are transferred into covalent dendronized polydiacetylenes, and the corresponding hydrogels show much improved mechanical properties with storage moduli about 10 kPa.

Structural and Property Characterizations of Dual-Responsive Core-Shell Tecto Dendrimers for Tumor Penetration and Gene Delivery Applications.

Core-shell tecto dendrimers (CSTDs) with excellent physicochemical properties and good tumor penetration and gene transfection efficiency have been demonstrated to have the potential to replace high-generation dendrimers in biomedical applications. However, their characterization and related biological properties of CSTDs for enhanced tumor penetration and gene delivery still lack in-depth investigation. Herein, three types of dual-responsive CSTDs are designed for thorough physicochemical characterization and investigation of their tumor penetration and gene delivery efficiency. Three types of CSTDs are prepared through phenylborate ester bonds of phenylboronic acid (PBA)-decorated generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers as cores and monose (galactose, glucose, or mannose)-conjugated G3 PAMAM dendrimers as shells and thoroughly characterized via NMR and other techniques. It is shown that the produced CSTDs display strong correlation signals between the PBA and monose protons, similar hydrodynamic diameters, and dual reactive oxygen species- and pH-responsivenesses. The dual-responsive CSTDs are proven to have structure-dependent tumor penetration property and gene delivery efficiency in terms of small interference RNA for gene silencing and plasmid DNA for gene editing, thus revealing a great potential for different biomedical applications.