Smart Drug Delivery Research Articles

A sustained release of alendronate from an injectable tetra-PEG hydrogel for efficient bone repair.

Significant efforts on construction of smart drug delivery for developing minimally invasive gelling system to prolong local delivery of bisphosphonates are considered as promising perspectives for the bone-related diseases, which provide the hydrogels with unique bioactivities for bone repair in clinic. Herein, we have constructed an alendronate (ALN)-conjoined injectable tetra-PEG hydrogel with excellent biocompatibility, uniform network, and favorable mechanical properties in one-pot strategy. In views of the quick ammonolysis reaction between N-hydroxysuccinimide (NHS)-ester of tetra-PEG-SG and amine groups of tetra-PEG-NH2 polymer and ALN molecules, the uniform networks were formed within seconds along with the easy injection, favorable biocompatibility and mechanical properties for hydrogel scaffolds. On account of the simultaneous physical encapsulation and chemical linkage of the ALN within the hydrogels, the ALN-conjoined tetra-PEG hydrogel exhibited a sustained drug release delivery that could persistently and effectively facilitate viability, growth, proliferation, and osteogenesis differentiation of stem cells, thereby allowing the consequent adaptation of hydrogels into the bone defects with irregular shapes, which endowed the ALN-conjoined tetra-PEG hydrogel with depot formulation capacity for governing the on-demand release of ALN drugs. Consequently, the findings imply that these drug-based tetra-PEG hydrogels mediate optimal release of therapeutic cargoes and effective promotion of in situ bone regeneration, which will be broadly utilized as therapeutic scaffolds in tissue engineering and regenerative medicine.

Promoting Re-epithelialization in an oxidative diabetic wound microenvironment using self-assembly of a ROS-responsive polymer and P311 peptide micelles

Engineering smart nano-therapeutics for re-epithelialisation of chronic wounds facilitates the wound healing process. However, due to excessive oxidative stress damage and persistent inflammation in diabetic wound microenvironment, the migration of stimulating epidermal cells in diabetic wounds represents a significant challenge. Here we synthesised P311-loaded micelles by self-assembly of P311 peptides and diblock copolymer poly (ethylene glycol)-block-poly (propylene sulfide) (PEG-b-PPS, denoted as PEPS) that have unique ability to transform an oxidative wound microenvironment into a proregenerative one while also providing cues for epidermal cell migration. The P311@PEPS showed an accelerated migration of epidermal cells via activation of the Akt signalling pathway, simultaneously suppressing the unfavourable oxidative wound microenvironment by scavenging reactive oxygen species (ROS), ultimately leading to the induction of an environment conducive to cell migration. Furthermore, the micelles were able to bypass the inhibitory effect of ROS on the Akt signalling pathway, thereby promoting epidermal cell migration. Additionally, we observed that diabetic wounds treated with P311@PEPS showed accelerated chronic wound healing, granulation tissue formation, collagen deposition and re-epithelialisation, thereby suggesting the efficacy of P311@PEPS as a promising nanoplatform for the treatment of chronic wounds. Statement of significanceBased on the unique conditions of the diabetic wound microenvironment, a smart drug delivery system with ROS-responsive nanomaterials has been widely investigated to enhance diabetic wound healing. In our previous studies, we observed that P311 promotes epidermal cell migration to induce wound re-epithelialisation. However, the application of P311 suffers from its instability. Herein, we developed a therapeutic platform with P311-loaded micelles (P311@PEPS), which were synthesized by the self-assembly of P311 peptides and diblock copolymer poly (ethylene glycol)-block-poly (propylene sulfide) (PEG-b-PPS, denoted as PEPS). These micelles provide continuous migration signals for epidermal cells by ROS-trigged P311 release. Additionally, P311@PEPS scavenges excess ROS and provides a microenvironment that reduces inflammation, which could protect P311 from enzymatic degradation and improve the bioavailability of P311.

Applications of phase change materials in smart drug delivery for cancer treatment.

Phase change materials (PCMs) are materials that are stimulated by the external enthalpy change (temperature) to realize solid-liquid and liquid-solid phase transformation. Due to temperature sensitivity, friendly modification, and low toxicity, PCMs have been widely used in smart drug delivery. More often than not, the drug was encapsulated in a solid PCMs matrix, a thermally responsive material. After the trigger implementation, PCMs change into a solid-liquid phase, and the loading drug is released accordingly. Therefore, PCMs can achieve precise release control with different temperature adjustments, which is especially important for small molecular drugs with severe side effects. The combination of drug therapy and hyperthermia through PCMs can achieve more accurate and effective treatment of tumor target areas. This study briefly summarizes the latest developments on PCMs as smart gate-keepers for anti-tumor applications in light of PCMs becoming a research hot spot in the nanomedicine sector in recent years.

Engineered Magnetic Polymer Nanoparticles Can Ameliorate Breast Cancer Treatment Inducing Pyroptosis-Starvation along with Chemotherapy.

Nanotechnology has shown a revolution in cancer treatments, including breast cancers. However, there remain some challenges and translational hurdles. Surgery, radiotherapy, and chemotherapy are the primary treatment methods for breast cancer, although drug combinations showed promising results in preclinical studies. Herein we report the development of a smart drug delivery system (DDS) to efficiently treat breast cancer by pyroptosis-starvation-chemotherapeutic combination. Cancer-starvation agent glucose oxidase was chemically attached to synthesized iron oxide nanoparticles which were entrapped inside poly(lactic-co-glycolic acid) along with apoptosis-associated speck-like protein containing a caspase recruitment domain plasmid and paclitaxel (PTX). An emulsion solvent evaporation method was used to prepare the DDS. The surface of the DDS was modified with chitosan to which aptamer was attached to achieve site-specific targeting. Hence, the prepared DDS could be targeted to a tumor site by both external magnet and aptamer to obtain an enhanced accumulation of drugs at the tumor site. The final size of the aptamer-decorated DDS was less than 200 nm, and the encapsulation efficiency of PTX was 76.5 ± 2.5%. Drug release from the developed DDS was much higher at pH 5.5 than at pH 7.4, ensuring the pH sensitivity of the DDS. Due to efficient dual targeting of the DDS, in vitro viability of 4T1 cells was reduced to 12.1 ± 1.6%, whereas the nontargeted group and free PTX group could reduce the viability of cells to 29.2 ± 2.4 and 46.2 ± 1.6%, respectively. Our DDS showed a synergistic effect in vitro and no severe side effects in vivo. This DDS has strong potential to treat various cancers.

Nanotechnology in reproduction, breeding and conservation of fish biodiversity: Current status and future potential

AbstractThe reproductive capability of an organism is the main factor to determine the stability of the population. Till now, numerous reproductive strategies have been used, to successfully breed the fish in captivity but the desired performance is yet to be achieved. Nanotechnology has transformed the reproductive capacity of higher animals to a greater extent and has a huge potential in the aquaculture sector too. The use of nanotechnology in fish reproduction and breeding is limited to the delivery of drugs, hormones, vaccines, or genes and still, an immense scope is left in the area that needs to be explored. Here, the recent progress of nanotechnology in fish reproduction, breeding and conservation of germplasm is reviewed. Further, the key successes in the development of cryopreservation, semen imaging, sperm sorting, germplasm preservation, prototypes of smart nanobiosensors and drug delivery systems in animals including fish are highlighted. The potential future opportunities for nanotechnology to enhance reproductive output and conservative management of fish have been presented. In general, the current review summarises some of the applications of nanotechnology that are performing well in higher animals and could be a game‐changer in manipulating the reproductive potential or conserving the fish germplasm.

Plasma-bioresource-derived multifunctional porous NGQD/AuNP nanocomposites for water monitoring and purification

Multifunctional metal–organic composites with controlled structures and properties are attractive for smart optoelectronic, drug delivery, cancer therapy, clean energy, and environmental applications. Here we develop lightweight, porous metal-graphene composites with uniformly dispersed nitrogen-doped graphene quantum dots (NGQDs) and gold nanoparticles (AuNPs) using reactive non-thermal microplasmas under ambient conditions. Synergy of NGQDs and AuNPs accelerates the polymer cross-linking during synthesis and ensures the requisite properties for simultaneous water monitoring and purification including reliable photoluminescence for heavy metal detection, as well as high adsorption capacity and fast catalytic degradation of organic pollutants. Large-area hierarchical composites with tunable porosity and self-healing ability can be fabricated by the fast and scalable plasma process avoiding toxic chemicals and high temperatures. The composite achieves 120 g g−1 water purification within 60 min at 0.13 mM 4-nitrophenol concentration and is able to monitor the water quality against Hg2+ with the detection limit of 2.2 μM, producing 2880 L kg−1 freshwater per day. Besides, almost 100 % of recalcitrant dye, remazol brilliant blue R, with the concentration of 20 ppm can be adsorbed by the composite in 120 min. Our work provides new insights into design and production of high-performance graphene-metal composites for emerging applications.

Fabrication of a smart drug delivery system based on hollow Ag2S@mSiO2 nanoparticles for fluorescence-guided synergistic photothermal chemotherapy.

A novel near-infrared (NIR) light-triggered smart nanoplatform has been developed for cancer targeting and imaging-guided combined photothermal-chemo treatment. Notably, Ag2S has a dual function of photothermal therapy and fluorescence imaging, which greatly simplifies the structure of the system. It can emit fluorescence at 820nm under an excitation wavelength of 560nm. The phase-change molecule of 1-tetradecanol (TD) is introduced as a temperature-sensitive gatekeeper to provide the nanocarrier with controlled release capability of doxorubicin (DOX). The nanocarrier (HAg2S@mSiO2-TD/DOX) shows a high drug loading capacity of 26.3% and exhibits an apparent NIR-responsive DOX release property. Under NIR irradiation, the photothermal effect of HAg2S nanocores facilitated the release of DOX through the melting of TD. The cytotoxicity test shows that the nanocarriers have good biocompatibility. As the same time, the synergistic combination leads to a better cancer inhibition effect than individual therapy alone in vitro. Cell uptake tests indicate that the carriers have excellent fluorescence imaging ability and high cellular uptake for HepG2 cells. This work provides a new strategy for the fabrication of smart nanocarriers with simple structures for fluorescence-mediated combination cancer therapy. Fabrication of a smart drug delivery system based on hollow Ag2S@mSiO2 nanoparticles for fluorescence-guided synergistic photothermal chemotherapy.

Development of Polymeric-Based Formulation as Potential Smart Colonic Drug Delivery System.

Conventional oral formulations are mainly absorbed in the small intestine. This limits their use in the treatment of some diseases associated with the colon, where the drug has to act topically at the inflammation site. This paved the way for the development of a smart colonic drug delivery system, thereby improving the therapeutic efficacy, reducing the dosing frequency and potential side effects, as well as improving patient acceptance, especially in cases where enemas or other topical preparations may not be effective alone in treating the inflammation. In healthy individuals, it takes an oral medication delivery system about 5 to 6 h to reach the colon. A colonic drug delivery system should delay or prohibit the medication release during these five to six hours while permitting its release afterward. The main aim of this study was to develop a smart drug delivery system based on pH-sensitive polymeric formulations, synthesized by a free-radical bulk polymerization method, using different monomer and crosslinker concentrations. The formulations were loaded with 5-amino salicylic acid as a model drug and Capmul MCM C8 as a bioavailability enhancer. The glass transition temperature (Tg), tensile strength, Young’s modulus, and tensile elongation at break were all measured as a part of the dried films’ characterization. In vitro swelling and release studies were performed to assess the behavior of the produced formulations. The in vitro swelling and release evaluation demonstrated the potential ability of the developed system to retard the drug release at conditions mimicking the stomach and small intestine while triggering its release at conditions mimicking the colon, which indicates its promising applicability as a potential smart colonic drug delivery system.

Ultrasound Triggering of Liposomal Nanodrugs for Cancer Therapy: A Review.

Efficient conventional chemotherapy is limited by its nonspecific nature, which causes severe systemic toxicity that can lead to patient discomfort and low therapeutic efficacy. The emergence of smart drug delivery systems (SDDSs) utilizing nanoparticles as drug nanocarriers has shown great potential in enhancing the targetability of anticancer agents and limiting their side effects. Liposomes are among the most investigated nanoplatforms due to their promising capabilities of encapsulating hydrophilic, lipophilic, and amphiphilic drugs, biocompatibility, physicochemical and biophysical properties. Liposomal nanodrug systems have demonstrated the ability to alter drugs’ biodistribution by sufficiently delivering the entrapped chemotherapeutics at the targeted diseased sites, sparing normal cells from undesired cytotoxic effects. Combining liposomal treatments with ultrasound, as an external drug release triggering modality, has been proven effective in spatially and temporally controlling and stimulating drug release. Therefore, this paper reviews recent literature pertaining to the therapeutic synergy of triggering nanodrugs from liposomes using ultrasound. It also highlights the effects of multiple physical and chemical factors on liposomes’ sonosensetivity, several ultrasound-induced drug release mechanisms, and the efficacy of ultrasound-responsive liposomal systems in cancer therapy. Overall, liposomal nanodrug systems triggered by ultrasound are promising cancer therapy platforms that can potentially alleviate the detriments of conventional cancer treatments.

An update on dual targeting strategy for cancer treatment.

The key issue in the treatment of solid tumors is the lack of efficient strategies for the targeted delivery and accumulation of therapeutic cargoes in the tumor microenvironment (TME). Targeting approaches are designed for more efficient delivery of therapeutic agents to cancer cells while minimizing drug toxicity to normal cells and off-targeting effects, while maximizing the eradication of cancer cells. The highly complicated interrelationship between the physicochemical properties of nanoparticles, and the physiological and pathological barriers that are required to cross, dictates the need for the success of targeting strategies. Dual targeting is an approach that uses both purely biological strategies and physicochemical responsive smart delivery strategies to increase the accumulation of nanoparticles within the TME and improve targeting efficiency towards cancer cells. In both approaches, either one single ligand is used for targeting a single receptor on different cells, or two different ligands for targeting two different receptors on the same or different cells. Smart delivery strategies are able to respond to triggers that are typical of specific disease sites, such as pH, certain specific enzymes, or redox conditions. These strategies are expected to lead to more precise targeting and better accumulation of nano-therapeutics. This review describes the classification and principles of dual targeting approaches and critically reviews the efficiency of dual targeting strategies, and the rationale behind the choice of ligands. We focus on new approaches for smart drug delivery in which synthetic and/or biological moieties are attached to nanoparticles by TME-specific responsive linkers and advanced camouflaged nanoparticles.

Digital Pills with Ingestible Sensors: Patent Landscape Analysis.

The modern healthcare system is directly related to the development of digital health tools and solutions. Pills with digital sensors represent a highly innovative class of new pharmaceuticals. The aim of this work was to analyze the patent landscape and to systematize the main trends in patent protection of digital pills with ingestible sensors worldwide; accordingly, to identify the patenting leaders as well as the main prevailing areas of therapy for patent protection, and the future perspectives in the field. In July 2022, a search was conducted using Internet databases, such as the EPO, USPTO, FDA and the Lens database. The patent landscape analysis shows an increase in the number of patents related to digital pills with ingestible sensors for mobile clinical monitoring, smart drug delivery, and endoscopy diagnostics. The leaders in the number of patents issued are the United States, the European Patent Office, Canada, Australia, and China. The following main areas of patenting digital pills with ingestible sensors were identified: treatment in the field of mental health; HIV/AIDS; pain control; cardiovascular diseases; diabetes; gastroenterology (including hepatitis C); oncology; tuberculosis; and transplantology. The development of scientific and practical approaches towards the implementation of effective and safe digital pills will improve treatment outcomes, increase compliance, reduce hospital stays, provide mobile clinical monitoring, have a positive impact on treatment costs and will contribute to increased patient safety.

Redox-Responsive Polymersomes as Smart Doxorubicin Delivery Systems.

Stimuli-responsive polymersomes have emerged as smart drug delivery systems for programmed release of highly cytotoxic anticancer agents such as doxorubicin hydrochloride (Dox·HCl). Recently, a biodegradable redox-responsive triblock copolymer (mPEG–PDH–mPEG) was synthesized with a central hydrophobic block containing disulfide linkages and two hydrophilic segments of poly(ethylene glycol) methyl ether. Taking advantage of the self-assembly of this amphiphilic copolymer in aqueous solution, in the present investigation we introduce a solvent-exchange method that simultaneously achieves polymersome formation and drug loading in phosphate buffer saline (10 mM, pH 7.4). Blank and drug-loaded polymersomes (5 and 10 wt.% feeding ratios) were prepared and characterized for morphology, particle size, surface charge, encapsulation efficiency and drug release behavior. Spherical vesicles of uniform size (120–190 nm) and negative zeta potentials were obtained. Dox·HCl was encapsulated into polymersomes with a remarkably high efficiency (up to 98 wt.%). In vitro drug release studies demonstrated a prolonged and diffusion-driven release at physiological conditions (~34% after 48 h). Cleavage of the disulfide bonds in the presence of 50 mM glutathione (GSH) enhanced drug release (~77%) due to the contribution of the erosion mechanism. Therefore, the designed polymersomes are promising candidates for selective drug release in the reductive environment of cancer cells.

Magnetic Nanochain-Based Smart Drug Delivery System with Remote Tunable Drug Release by a Magnetic Field

Magnetic Nanochain-Based Smart Drug Delivery System with Remote Tunable Drug Release by a Magnetic Field

Nanocarriers for delivery of siRNA as gene silencing mediator.

The term nanocarrier refers to sub-micrometric particles of less than 100 nm, designed to transport, distribute, and release nanotechnology-based drug delivery systems. siRNA therapy is a novel strategy that has great utility for a variety of treatments, however naked siRNA delivery has not been an effective strategy, resulting in the necessary use of nanocarriers for delivery. This review aims to highlight the versatility of carriers based on smart drug delivery systems. The nanocarriers based on nanoparticles as siRNA DDS have provided a set of very attractive advantages related to improved physicochemical properties, such as high surface-to-volume ratio, versatility to package siRNA, provide a dual function to both protect extracellular barriers that lead to elimination and overcome intracellular barriers limiting cytosolic delivery, and possible chemical modifications on the nanoparticle surface to improve stability and targeting. Lipid and polymeric nanocarriers have proven to be stable, biocompatible, and effective in vitro, further exploration of the development of new nanocarriers is needed to obtain safe and biocompatible tools for effective therapy.

Cubosomes: Design, Development, and Tumor-Targeted Drug Delivery Applications.

Because of the extraordinary advancements in biomedical nanotechnology over the last few decades, traditional drug delivery systems have been transformed into smart drug delivery systems that respond to stimuli. These well-defined nanoplatforms can boost therapeutic targeting efficacy while reducing the side effects/toxicities of payloads, which are crucial variables for enhancing patient compliance by responding to specific internal or external triggers. Cubosomes are lipid-based nano systems that are analogous to well-known vesicular systems, such as lipo- and niosomes. They could be used as part of a unique drug delivery system that includes hydro-, lipo-, and amphiphilic drug molecules. In this review, we critically analyze the relevant literature on cubosomesregarding theories of cubosomeself-assembly, composition, and manufacturing methods, with an emphasis on tumor-targeted drug delivery applications. Due to the bioadhesive and -compatible nature of cubosome dispersion, this review also focuses on a variety of drug delivery applications, including oral, ophthalmic and transdermal.

PNA-ATP aptamer-capped doxorubicin-loaded silica nanoparticles for targeted cancer therapy

Nanomaterial-based drug delivery has opened new horizons in cancer therapy. This study aimed to investigate the in vitro and in vivo anti-cancer effects of a hyaluronic acid (HA)-targeted nanocarrier based on hollow silica nanoparticles (HSNPs), gated with peptide nucleic acid (PNA) and ATP aptamer (ATPApt) and loaded with doxorubicin (DOX). After formulation of a smart drug delivery nanosystem (HSNPs/DOX/ATPApt/PNA/HA), drug release, cytotoxicity, uptake, and in vivo anti-tumor properties were studied. Drug release test showed the controlled release of encapsulated DOX in response to ATP content. MTT and flow cytometry indicated that HA could improve both cytotoxicity and cellular uptake of the formulation. Moreover, HA-targeted formulation enhanced both the survival rate and tumor inhibition in the tumor-bearing mice compared with free DOX (P < 0.05). Our findings confirmed that HA-targeted nanoformulation, gated with PNA/aptamer and loaded with DOX can provide a novel therapeutic platform with great potential for cancer therapy.

Liposomes: A Promising Strategy to Treat Multidrug Resistance in Cancers

Drug resistance has become a main concern in the cancer therapy worldwide. It can be a temporary or permanent potential of an organismto multiply even in the presence of the lethal drug concentration.Generally, multidrug resistance (MDR) is associated with the over-expression of P-glycoprotein(P-gp), resulting in amplified efflux of anticancer drug molecules from cancer cells [1]. Therefore, interrupting the P-gp efflux might be an effective strategy to resolve the MDR in cancer patients. Interestingly, smart nano-sized transporters can deliver the drug cargo at the proposed site and release the drug precisely to elicit desirable therapeutic response. Thanks to their small diameter, large surface area. Now a days, researchers have explored a smart drug delivery system known as polymer lipid hybrid nanoparticles, which are capable to combat various diseases [2,3]. Over expressed ATP-Binding Cassette (ABC) transporters is frequently associated with MDR in cancer treatments. However, no approved anti-cancer drug molecules are available for clinical use in order to reverse MDR by obstructing P-glycoprotein. However, MDR is responsible for the low intracellular drug concentrations ultimately reduce the cytotoxicity of a broad spectrum of antitumor drugs including anthracyclines (e.g. DOX), vinca alkaloids (e.g. vincristine), podophyllotoxins (e.g. etoposide) and taxanes (e.g. taxol) [4].

Prenylated Flavonoids in Topical Infections and Wound Healing.

The review presents prenylated flavonoids as potential therapeutic agents for the treatment of topical skin infections and wounds, as they can restore the balance in the wound microenvironment. A thorough two-stage search of scientific papers published between 2000 and 2022 was conducted, with independent assessment of results by two reviewers. The main criteria were an MIC (minimum inhibitory concentration) of up to 32 µg/mL, a microdilution/macrodilution broth method according to CLSI (Clinical and Laboratory Standards Institute) or EUCAST (European Committee on Antimicrobial Susceptibility Testing), pathogens responsible for skin infections, and additional antioxidant, anti-inflammatory, and low cytotoxic effects. A total of 127 structurally diverse flavonoids showed promising antimicrobial activity against pathogens affecting wound healing, predominantly Staphylococcus aureus strains, but only artocarpin, diplacone, isobavachalcone, licochalcone A, sophoraflavanone G, and xanthohumol showed multiple activity, including antimicrobial, antioxidant, and anti-inflammatory along with low cytotoxicity important for wound healing. Although prenylated flavonoids appear to be promising in wound therapy of humans, and also animals, their activity was measured only in vitro and in vivo. Future studies are, therefore, needed to establish rational dosing according to MIC and MBC (minimum bactericidal concentration) values, test potential toxicity to human cells, measure healing kinetics, and consider formulation in smart drug release systems and/or delivery technologies to increase their bioavailability.

Green synthesized-silver nanoparticles coated with targeted chitosan nanoparticles for smart drug delivery

The ever-increasing rate of people with colon cancer due to inappropriate diet and pollution in the industrial world leads to practical attempts by scientists to arrest it. In this work, we developed folic acid (FA) functionalized chitosan (CS) nanoparticles to co-delivery of imatinib (I) and silver (Ag) nanoparticles to HCT116 colon cancer cells. After efficient synthesis of FA–CS–Ag-I nanocomposite, various analytical devices including FT-IR, XRD, DLS, TEM, and SEM were used for qualification and quantification of the nanocomposite. Drug release study was demonstrated controlled release in normal pH (less than 20% after 24 h) and fast release in pH 5.0 (about 80% release after 24 h). In biomedical tests, MTT assay indicated excellent suppression against cancer cells, about 20% cell viability after 24 h of incubation with 20 nM concentration while it was over 70% cell viability for HFF1 cell at the same conditions. The BAX, Bcl2, BECLIN1, mTORC1 and ATG5 gene expression (for instance, a 5-fold and a 3-fold increase in expression of BAX and mTORC1 after incubation with 5 nM of FA–CS–Ag-I, respectively), apoptosis (65% and 42% apoptosis for Ag and FA–CS–Ag-I samples, respectively), and cell cycle arrest (24% and 12% cell cycle arrest for Ag and FA–CS–Ag-I samples, respectively) analyses have further confirmed the apoptosis-inducing ability of FA–CS–Ag-I and even Ag nanoparticles. These data have been depicted that FA–CS–Ag-I can potentially apply for active delivery of therapeutics against colon cancer.

Matrix metalloproteinase-directed precise targeting and smart drug delivery of biodegradable gold nanodandelions as CT imaging guided anticancer therapy

Systemic adverse effects and poor accumulation at tumor sites constitute important limitations of current chemotherapy in the battle against the majority of cancers. Even though utilization of nanoparticle technology is the preferred treatment modality for improving drug delivery efficiency, achieving controlled drug release and image-guided therapy still pose challenges. In this paper, we developed a tumor microenvironment-responsive gold nanodandelions encapsulating doxorubicin (GNDs@gelatin/DOX) for tumor-targeted imaging and drug delivery. High surface-area GNDs were prepared through a gelatin-mediated process which showed great DOX-loading efficiency. Specifically, GNDs@gelatin/DOX is cleavable by gelatinase (e.g., matrix metalloproteinases −2 and −9) to release the cancer therapeutic agent and aggregate in tissues where these enzymes are upregulated. We demonstrate that GNDs@gelatin/DOX accumulated preferentially in matrix metalloproteinases-2/-9 (MMP-2/-9) overexpressed tumor after intravenous injection, which is useful for computed tomography (CT) imaging-guided chemotherapeutics. Intriguingly, GNDs@gelatin/DOX exhibited the capacity to control and prolong Dox release induced suppression of tumor growth and less cardiotoxicity compared with conventional doxorubicin. In addition, our results show that the alternation of tissue inhibitors of metalloproteinases (TIMP) can attenuate MMP activity, and thus reduce the sensitivity of cancer cells to chemotherapeutics. It is noteworthy that in vivo CT imaging and subsequent inductively coupled plasma-mass spectroscopy (ICP-MS) of harvested tissues revealed that GNDs was found to transport into the gastrointestinal tract and substantial elimination from the mice with prolonged time. In aggregate, GNDs@gelatin/DOX is a highly promising chemotheranostic agent for clinical translation.