Immune Cell‐Mediated Biodegradable Theranostic Nanoparticles for Melanoma Targeting and Drug Delivery

Although tremendous efforts have been made on targeted drug delivery systems, current therapy outcomes still suffer from low circulating time and limited targeting efficiency. The integration of cell‐mediated drug delivery and theranostic nanomedicine can potentially improve cancer management in both therapeutic and diagnostic applications. By taking advantage of innate immune cell's ability to target tumor cells, the authors develop a novel drug delivery system by using macrophages as both nanoparticle (NP) carriers and navigators to achieve cancer‐specific drug delivery. Theranostic NPs are fabricated from a unique polymer, biodegradable photoluminescent poly (lactic acid) (BPLP‐PLA), which possesses strong fluorescence, biodegradability, and cytocompatibility. In order to minimize the toxicity of cancer drugs to immune cells and other healthy cells, an anti‐BRAF V600E mutant melanoma specific drug (PLX4032) is loaded into BPLP‐PLA nanoparticles. Muramyl tripeptide is also conjugated onto the nanoparticles to improve the nanoparticle loading efficiency. The resulting nanoparticles are internalized within macrophages, which are tracked via the intrinsic fluorescence of BPLP‐PLA. Macrophages carrying nanoparticles deliver drugs to melanoma cells via cell–cell binding. Pharmacological studies also indicate that the PLX4032 loaded nanoparticles effectively kill melanoma cells. The “self‐powered” immune cell‐mediated drug delivery system demonstrates a potentially significant advancement in targeted theranostic cancer nanotechnologies.     

Advanced Subcompartmentalized Microreactors: Polymer Hydrogel Carriers Encapsulating Polymer Capsules and Liposomes

The design of compartmentalized carriers for advanced drug delivery systems or artificial cells and organelles is of interest for biomedical applications. Herein, a polymer carrier microreactor that contains two different classes of subcompartments, multilayered polymer capsules and liposomes, is presented. 50 nm‐diameter liposomes and 300 nm‐diameter polymer capsules are encapsulated into a larger polymer carrier capsule, demonstrating control over the spatial positioning of the subcompartments, which are either ‘membrane‐associated’ or 'free‐floating’ in the aqueous interior. Selective and spatially dependent degradation of the 300 nm‐diameter subcompartments (without destroying the structural integrity of the enzyme‐loaded liposomes) is also shown, by performing an encapsulated enzymatic reaction using the liposomal subcompartments. These findings cover several important aspects toward the development of engineered compartmentalized carrier vessels for the creation of artificial cell mimics or advanced therapeutic delivery systems.     

DNA Nanostructures as Pt(IV) Prodrug Delivery Systems to Combat Chemoresistance

Cisplatin is a first‐line drug in clinical cancer treatment but its efficacy is often hindered by chemoresistance in cancer cells. Reduced intracellular drug accumulation is revealed to be a major mechanism of cisplatin resistance. Nanoscale drug delivery systems could help to overcome this problem because of their more active cellular uptake and more accurate tumor localization. DNA nanostructures have emerged as promising drug delivery systems because of their intrinsic biocompatibility and structural programmability. Herein, three diverse DNA nanostructures are constructed and their potential for cisplatin prodrug delivery is investigated. Results found that these DNA nanostructures could remarkably enhance the cellular internalization of platinum drugs and thus increase the anticancer activity, not only to regular lung cancer cells (A549), but more importantly to cisplatin‐resistant cancer cells (A549cisR). Further, in vivo studies also demonstrate that cisplatin prodrug loaded DNA nanostructures could effectively suppress tumor growth in both regular and cisplatin‐resistant tumor models. This study suggests that DNA nanostructures are effective carriers for platinum prodrug delivery to combat chemoresistance.     

Dual pH/ROS‐Responsive Nanoplatform with Deep Tumor Penetration and Self‐Amplified Drug Release for Enhancing Tumor Chemotherapeutic Efficacy

Poor deep tumor penetration and incomplete intracellular drug release remain challenges for antitumor nanomedicine application in clinical settings. Herein, a nanomedicine (RLPA‐NPs) is developed that can achieve prolonged blood circulation, deep tumor penetration, active‐targeting of cancer cells, endosome/lysosome escape, and intracellular selectivity self‐amplified drug release for effective drug delivery. The RLPA‐NPs are constructed by encapsulation of a pH‐sensitive polymer octadecylamine‐poly(aspartate‐1‐(3‐aminopropyl) imidazole) (OA‐P(Asp‐API)) and a ROS‐generation agent, β‐Lapachone (Lap), in micelles assembled by the tumor‐penetration peptide internalizing RGD (iRGD)‐modified ROS‐responsive paclitaxel (PTX)‐prodrug. iRGD could promote RLPA‐NPs penetration into deep tumor tissue, and specific targeting to cancer cells. After internalization by cancer cells through receptor‐mediated endocytosis, OA‐P(Asp‐API) can rapidly protonate in the endosome's acidic environment, resulting in RLPA‐NPs escape from the endosome through the “proton sponge effect”. At the same time, the RLPA‐NPs micelle disassembles, releasing Lap and PTX‐prodrug. Subsequently, the released Lap could generate ROS, consequently amplifying and accelerating PTX release to kill tumor cells. The in vitro and in vivo studies demonstrated that RLPA‐NPs can significantly improve the therapeutic effect compared to control groups. Therefore, RLPA‐NPs are a promising nanoplatform for overcoming multiple physiological and pathological barriers to enhance drug delivery.     

Site‐Specific Construction of Long‐Term Drug Depot for Suppression of Tumor Recurrence

Local tumor recurrence after surgical resection is a critical concern in cancer therapy, and the current treatments, such as postsurgical chemotherapy, still show undesired side effects. Here a nonimplant strategy (transformation induced localization, TIL) is presented to in situ construct long‐term retentive drug depots, wherein the sustained drug release from fibrous drug depots results in highly efficient suppression of postsurgical local tumor relapse. The peptide‐based prodrug nanoparticles show favorable tumor targeting and instantly reorganize into fibrous nanostructures under overexpressed enzyme, realizing the construction of long‐term drug depot in the tumor site. After the resection surgery, the remnant cancer cells are still inhibited by the sustained drug release from the fibrous prodrug depot, effectively preventing postsurgical local recurrences. This TIL strategy shows great potential in cancer recurrence therapy and offers a novel perspective for constructing functional biomaterials in vivo.     

Engineering Extracellular Vesicles with the Tools of Enzyme Prodrug Therapy

Extracellular vesicles (EVs) have recently gained significant attention as important mediators of intercellular communication, potential drug carriers, and disease biomarkers. These natural cell‐derived nanoparticles are postulated to be biocompatible, stable under physiological conditions, and to show reduced immunogenicity as compared to other synthetic nanoparticles. Although initial clinical trials are ongoing, the use of EVs for therapeutic applications may be limited due to undesired off‐target activity and potential “dilution effects” upon systemic administration which may affect their ability to reach their target tissues. To fully exploit their therapeutic potential, EVs are embedded into implantable biomaterials designed to achieve local delivery of therapeutics taking advantage of enzyme prodrug therapy (EPT). In this first application of EVs for an EPT approach, EVs are used as smart carriers for stabilizing enzymes in a hydrogel for local controlled conversion of benign prodrugs to active antiinflammatory compounds. It is shown that the natural EVs' antiinflammatory potential is comparable or superior to synthetic carriers, in particular upon repeated long‐term incubations and in different macrophage models of inflammation. Moreover, density‐dependent color scanning electron microscopy imaging of EVs in a hydrogel is presented herein, an impactful tool for further understanding EVs in biological settings.     

A cell-delivered and cell-activated SN38-dextran prodrug increases survival in a murine disseminated pancreatic cancer model

Enzyme‐activated prodrugs have been investigated and sought after as highly specific, low‐side‐effect treatments, especially for cancer therapy. Unfortunately, excellent targets for enzyme‐activated therapy are rare. Here a system based on cell delivery that can carry both a prodrug and an activating enzyme to the cancer site is demonstrated. Raw264.7 cells (mouse monocyte/macrophage‐like cells, Mo/Ma) are engineered to express intracellular rabbit carboxylesterase (InCE), which is a potent activator of the prodrug irinotecan to SN38. InCE expression is regulated by the TetOn® system, which silences the gene unless a tetracycline, such as doxycycline, is present. Concurrently, an irinotecan‐like prodrug, which is conjugated to dextran and can be loaded into the cytoplasm of Mo/Ma, is synthesized. To test the system, a murine pancreatic cancer model is generated by intraperitoneal (i.p.) injection of Pan02 cells. Engineered Mo/Ma are loaded with the prodrug and are injected i.p. Two days later, doxycycline was given i.p. to activate InCE, which activated the prodrug. A survival study demonstrates that this system significantly increased survival in a murine pancreatic cancer model. Thus, for the first time, a prodrug/activating enzyme system, which is self‐contained within tumor‐homing cells and can prolong the life of i.p. pancreatic tumor bearing mice, is demonstrated.     

Bioinspired Nano‐Prodrug with Enhanced Tumor Targeting and Increased Therapeutic Efficiency

Nanotechnology‐based drug delivery has a great potential to revolutionize cancer treatment by enhancing anticancer drug efficacy and reducing drug toxicity. Here, a bioinspired nano‐prodrug (BiNp) assembled by an antineoplastic peptidic derivative (FA‐KLA‐Hy‐DOX), a folate acid (FA)‐incorporated proapoptotic peptide (KLAKLAK)₂ (KLA) to doxorubicin (DOX) via an acid‐labile hydrozone bond (Hy) is constructed. The hydrophobic antineoplastic agent DOX is efficiently shielded in the core of nano‐prodrug. With FA targeting moieties on the surface, the obtained BiNp shows significant tumor‐targeting ability and enhances the specific uptake of cancer cells. Upon the trigger by the intracellular acidic microenvironment of endosomes, the antineoplastic agent DOX is released on‐demand and promotes the apoptosis of cancer cells. Simultaneously, the liberated FA‐KLA can induce the dysfunction of mitochondria and evoke mitochondria‐dependent apoptosis. In vitro and in vivo results show that the nano‐prodrug BiNp with integrated programmed functions exhibits remarkable inhibition of tumor and achieves a maximized therapeutic efficiency with a minimized side effect.     

Scar Tissue‐Targeting Polymer Micelle for Spinal Cord Injury Treatment

Spinal cord injury (SCI) is a devastating disorder, leading to permanent motor and sensory deficit. Despite recent advances in neurosciences, the treatment efficacy on SCI patients remains unsatisfactory, mainly due to the poor accumulation, short retention, and lack of controlled release of therapeutics in lesion tissue. Herein, an injured spinal cord targeting prodrug polymer micelle is built. An esterase‐responsive bond is used to link apocynin (APO) monomer, because of the enhanced esterase activity found in microglia cells after activation, which ensures a controlled degradation of APO prodrug (Allyloxypolyethyleneglycol‐b‐poly [2‐(((4‐acetyl‐2‐methoxyphenoxy)carbonyl)oxy)ethyl methacrylate], APEG‐PAPO or PAPO) by activated microglia cells. A scar tissue‐homing peptide (cysteine‐alanine‐glutamine‐lysine, CAQK) is introduced to the PAPO to endow the polymer micelle the lesion tissue‐targeting ability. As a result, this CAQK‐modified prodrug micelle (cPAM) exhibits an improved accumulation and prolonged retention in lesion tissue compared to the control micelle. The cPAM also leads to superior tissue protection and sustained motor function recovery than the control groups in a mouse model of SCI. In conclusion, the cPAM induces an effective treatment of SCI by the lesion tissue specific delivery of the prodrug polymer via its robust scar binding effect, making the scar tissue a drug releasing platform for sustained treatment of SCI.     

Daunorubicin‐Loaded DNA Origami Nanostructures Circumvent Drug‐Resistance Mechanisms in a Leukemia Model

Many cancers show primary or acquired drug resistance due to the overexpression of efflux pumps. A novel mechanism to circumvent this is to integrate drugs, such as anthracycline antibiotics, with nanoparticle delivery vehicles that can bypass intrinsic tumor drug‐resistance mechanisms. DNA nanoparticles serve as an efficient binding platform for intercalating drugs (e.g., anthracyclines doxorubicin and daunorubicin, which are widely used to treat acute leukemias) and enable precise structure design and chemical modifications, for example, for incorporating targeting capabilities. Here, DNA nanostructures are utilized to circumvent daunorubicin drug resistance at clinically relevant doses in a leukemia cell line model. The fabrication of a rod‐like DNA origami drug carrier is reported that can be controllably loaded with daunorubicin. It is further directly verified that nanostructure‐mediated daunorubicin delivery leads to increased drug entry and retention in cells relative to free daunorubicin at equal concentrations, which yields significantly enhanced drug efficacy. Our results indicate that DNA origami nanostructures can circumvent efflux‐pump‐mediated drug resistance in leukemia cells at clinically relevant drug concentrations and provide a robust DNA nanostructure design that could be implemented in a wide range of cellular applications due to its remarkably fast self‐assembly (≈5 min) and excellent stability in cell culture conditions.     

Facile Fabrication of Tumor Redox‐Sensitive Nanoassemblies of Small‐Molecule Oleate Prodrug as Potent Chemotherapeutic Nanomedicine

The conjugate of paclitaxel (PTX) and docosahexaenoic acid has entered into clinical trials. However, the most recent clinical outcomes fell short of expectations, due to the extremely slow drug release from the hydrophobic conjugates. Herein, a novel prodrug‐based nanoplatform self‐assembled by the disulfide bond linked conjugates of PTX and oleic acid for rapid and differential release of PTX in tumor cells is reported. This redox‐responsive prodrug‐nanosystem demonstrates multiple therapeutic advantages, including one‐step facile fabrication, high drug‐loading efficiency (56%, w/w), on‐demand drug release responding to redox stimuli, as well as favorable cellular uptake and biodistribution. These advantages result in significantly enhanced antitumor efficacy in vivo, with the tumor almost completely disappearing in mice. Such a uniquely engineered prodrug‐nanosystem has great potential to be used as potent chemotherapeutic nanomedicine in clinical cancer therapy.     

Tumor Microenvironment‐Activatable Prodrug Vesicles for Nanoenabled Cancer Chemoimmunotherapy Combining Immunogenic Cell Death Induction and CD47 Blockade

Chemoimmunotherapy is reported to activate a robust T cell antitumor immune response by triggering immunogenic cell death (ICD), which has initiated a number of clinical trials. However, current chemoimmunotherapy is restricted to a small fraction of patients due to low drug delivery efficacy and immunosuppression within the tumor microenvironment. A tumor microenvironment‐activatable prodrug vesicle for cancer chemoimmunotherapy using ICD is herein reported. The prodrug vesicles are engineered by integrating an oxaliplatin (OXA) prodrug and PEGylated photosensitizer (PS) into a single nanoplatform, which show tumor‐specific accumulation, activation, and deep penetration in response to the tumoral acidic and enzymatic microenvironment. It is demonstrated that codelivery of OXA prodrug and PS can trigger ICD of the tumor cells by immunogenic cells killing. The combination of prodrug vesicle‐induced ICD with Î ± CD47‐mediated CD47 blockade further facilitates dendritic cell (DC) maturation, promotes antigen presentation by DCs, and eventually propagates the antitumor immunity of ICD. CD47 blockade and ICD induction efficiently inhibit the growth of both primary and abscopal tumors, suppress tumor metastasis, and prevent tumor recurrence. Collectively, these results imply that boosting antitumor immunity using ICD induction and suppressing tumor immune evasion via CD47 blockade might be promising for improved cancer chemoimmunotherapy.     

Inhibition of 3‐D Tumor Spheroids by Timed‐Released Hydrophilic and Hydrophobic Drugs from Multilayered Polymeric Microparticles

First‐line cancer chemotherapy necessitates high parenteral dosage and repeated dosing of a combination of drugs over a prolonged period. Current commercially available chemotherapeutic agents, such as Doxil and Taxol, are only capable of delivering single drug in a bolus dose. The aim of this study is to develop dual‐drug‐loaded, multilayered microparticles and to investigate their antitumor efficacy compared with single‐drug‐loaded particles. Results show hydrophilic doxorubicin HCl (DOX) and hydrophobic paclitaxel (PTX) localized in the poly(dl ‐lactic‐co‐glycolic acid, 50:50) (PLGA) shell and in the poly(l ‐lactic acid) (PLLA) core, respectively. The introduction of poly[(1,6‐bis‐carboxyphenoxy) hexane] (PCPH) into PLGA/PLLA microparticles causes PTX to be localized in the PLLA and PCPH mid‐layers, whereas DOX is found in both the PLGA shell and core. PLGA/PLLA/PCPH microparticles with denser shells allow better control of DOX release. A delayed release of PTX is observed with the addition of PCPH. Three‐dimensional MCF‐7 spheroid studies demonstrate that controlled co‐delivery of DOX and PTX from multilayered microparticles produces a greater reduction in spheroid growth rate compared with single‐drug‐loaded particles. This study provides mechanistic insights into how distinctive structure of multilayered microparticles can be designed to modulate the release profiles of anticancer drugs, and how co‐delivery can potentially provide better antitumor response.     

Inorganic materials as drug delivery systems in coronary artery stenting

Recent studies proved coronary stent implantation to be superior over conventional angioplasty in the treatment of coronary artery disease. However, restenosis remains one of the most crucial problems in interventional cardiology. Inflammatory infiltrates and foreign body reactions can be found in the tissue surrounding the struts in stenting. Thrombogenesis, proliferation of α‐actin expressing cells (smooth muscle cells) and hyperplasia of the intima occur. In order to improve the biocompatibility of the stents, new stent designs and stent coatings have been developed. One advantage of stent coating is the combination of mechanical stability of the stent with the biocompatibility of the coating. The coatings are divided into active and passive coatings. Passive coatings improve the biocompatibility of the stent, while active coatings may suppress neointima proliferation by releasing anti‐inflammatory or antiproliferative substances. Immunosuppressive drugs (tacrolimus, sirolimus) and cytostatic drugs (paclitaxel) have been tested in several studies and showed promising results. However, it could also be demonstrated that polymer‐coated stents used as a matrix for drug release reduced the hyperplasia of the intima. However, after dissipation of the immunosuppressants or cytostatics, the presence of the polymer itself lead to a delayed inflammation and proliferation causing restenosis. Thus, efforts have been made to develop inorganic coatings that are suitable for drug loading. One promising approach is a new nanoporous alumina coating. Preliminary tests with this coating revealed favourable loading characteristics and sustained drug release in vivo. The present article provides an overview on different approaches for stent coatings.     

pH‐ and NIR Light‐Responsive Polymeric Prodrug Micelles for Hyperthermia‐Assisted Site‐Specific Chemotherapy to Reverse Drug Resistance in Cancer Treatment

Despite the exciting advances in cancer chemotherapy over past decades, drug resistance in cancer treatment remains one of the primary reasons for therapeutic failure. IR‐780 loaded pH‐responsive polymeric prodrug micelles with near infrared (NIR) photothermal effect are developed to circumvent the drug resistance in cancer treatment. The polymeric prodrug micelles are stable in physiological environment, while exhibit fast doxorubicin (DOX) release in acidic condition and significant temperature elevation under NIR laser irradiation. Phosphorylcholine‐based biomimetic micellar shell and acid‐sensitive drug conjugation endow them with prolonged circulation time and reduced premature drug release during circulation to conduct tumor site‐specific chemotherapy. The polymeric prodrug micelles combined with NIR laser irradiation could significantly enhance intracellular DOX accumulation and synergistically induce the cell apoptosis in DOX‐resistant MCF‐7/ADR cells. Meanwhile, the tumor site‐specific chemotherapy combined with hyperthermia effect induces significant inhibition of MCF‐7/ADR tumor growth in tumor‐bearing mice. These results demonstrate that the well‐designed IR‐780 loaded polymeric prodrug micelles for hyperthermia‐assisted site‐specific chemotherapy present an effective approach to reverse drug resistance.     

PD‐1 Blockade for Improving the Antitumor Efficiency of Polymer–Doxorubicin Nanoprodrug

Chemotherapy is well recognized to induce immune responses during some chemotherapeutic drugs‐mediated tumor eradication. Here, a strategy involving blocking programmed cell death protein 1 (PD‐1) to enhance the chemotherapeutic effect of a doxorubicin nanoprodrug HA‐Psi‐DOX is proposed and the synergetic mechanism between them is further studied. The nanoprodrugs are fabricated by conjugating doxorubicin (DOX) to an anionic polymer hyaluronic acid (HA) via a tumor overexpressed matrix metalloproteinase sensitive peptide (CPLGLAGG) for tumor targeting and enzyme‐activated drug release. Once accumulated at the tumor site, the nanoprodrug can be activated to release antitumor drug by tumor overexpressed MMP‐2. It is found that HA‐Psi‐DOX nanoparticles can kill tumor cells effectively and initiate an antitumor immune response, leading to the upregulation of interferon‐γ. This cytokine promotes the expression of programmed cell death protein‐ligand 1 (PD‐L1) on tumor cells, which will cause immunosuppression after interacting with PD‐1 on the surface of lymphocytes. The results suggest that the therapeutic efficiency of HA‐Psi‐DOX nanoparticles is significantly improved when combined with checkpoint inhibitors anti‐PD‐1 antibody (α‐PD1) due to the neutralization of immunosuppression by blocking the interaction between PD‐L1 and PD‐1. This therapeutic system by combining chemotherapy and immunotherapy further increases the link between conventional tumor therapies and immunotherapy.     

Water‐Dispersible Fullerene Aggregates as a Targeted Anticancer Prodrug with both Chemo‐ and Photodynamic Therapeutic Actions

Prodrug therapy is one strategy to deliver anticancer drugs in a less reactive manner to reduce nonspecific cytotoxicity. A new multifunctional anticancer prodrug system based on water‐dispersible fullerene (C60) aggregates is introduced; this prodrug system demonstrates active targeting, pH‐responsive chemotherapy, and photodynamic therapeutic (PDT) properties. Incorporating (via a cleavable bond) an anticancer drug, which is doxorubicin (DOX) in this study, and a targeting ligand (folic acid) onto fullerene while maintaining an overall size of approximately 135 nm produces a more specific anticancer prodrug. This prodrug can enter folate receptor (FR)‐positive cancer cells and kill the cells via intracellular release of the active drug form. Moreover, the fullerene aggregate carrier exhibits PDT action; the cytotoxicity of the system towards FR‐positive cancer cells is increased in response to light irradiation. As the DOX drug molecules are conjugated onto fullerene, the DOX fluorescence is significantly quenched by the strong electron‐accepting capability of fullerene. The fluorescence restores upon release from fullerene, so this fluorescence quenching–restoring feature can be used to track intracellular DOX release. The combined effect of chemotherapy and PDT increases the therapeutic efficacy of the DOX–fullerene aggregate prodrug. This study provides useful insights into designing and improving the applicability of fullerene for other targeted cancer prodrug systems.     

Controlled Release of Antiproliferative Drugs From Polymeric Systems for Stent Applications and Local Cancer Treatment

Restenosis (re‐narrowing of the blood vessel wall) and cancer are two different pathologies that have drawn extensive research attention over the years. Antiproliferative drugs such as paclitaxel inhibit cell proliferation and are therefore effective in the treatment of cancer as well as neointimal hyperplasia, which is known to be the main cause of restenosis. Drug‐eluting stents (DES) significantly reduce the incidence of in‐stent restenosis (ISR), which was once considered a major adverse outcome of percutaneous coronary stent implantations. Localized release of antiproliferative drugs interferes with the pathological proliferation of vascular smooth muscle cells (VSMC), which is the main cause of ISR. Conventional approaches to treating cancer are mainly surgical excision, irradiation, and chemotherapy. In cancer therapy, surgical treatment is usually performed on patients with a resectable carcinoma. An integrated therapeutic approach, such as the addition of a delivery system loaded with an antiproliferative drug at the tumor resection site, is desirable. This will provide a high local concentration of a drug, that is, detrimental to malignant cells which may have survived surgery, thus preventing re‐growth and metastasis of the tumor. The present review describes recent advances in systems for controlled release of antiproliferative agents. It describes basic concepts in drug delivery systems and antiproliferative drugs and then focuses on both types of systems: stents with controlled release of antiproliferative agents, and drug‐eluting particles and implants for local cancer treatment. The last part of this article is dedicated to our novel drug‐eluting composite fiber structures, which can be used as basic stent elements as well as for local cancer treatment.     

Therapeutic‐Gas‐Responsive Hydrogel

Nitric oxide (NO) is a crucial signaling molecule with various functions in physiological systems. Due to its potent biological effect, the preparation of responsive biomaterials upon NO having temporally transient properties is a challenging task. This study represents the first therapeutic‐gas (i.e., NO)‐responsive hydrogel by incorporating a NO‐cleavable crosslinker. The hydrogel is rapidly swollen in response to NO, and not to other gases. Furthermore, the NO‐responsive gel is converted to enzyme‐responsive gels by cascade reactions from an enzyme to NO production for which the NO precursor is a substrate of the enzyme. The application of the hydrogel as a NO‐responsive drug‐delivery system is proved here by revealing effective protein drug release by NO infusion, and the hydrogel is also shown to be swollen by the NO secreted from the cultured cells. The NO‐responsive hydrogel may prove useful in many applications, for example drug‐delivery vehicles, inflammation modulators, and as a tissue scaffold.     

Selective CXCR4+ Cancer Cell Targeting and Potent Antineoplastic Effect by a Nanostructured Version of Recombinant Ricin

Under the unmet need of efficient tumor‐targeting drugs for oncology, a recombinant version of the plant toxin ricin (the modular protein T22‐mRTA‐H6) is engineered to self‐assemble as protein‐only, CXCR4‐targeted nanoparticles. The soluble version of the construct self‐organizes as regular 11 nm planar entities that are highly cytotoxic in cultured CXCR4⁺ cancer cells upon short time exposure, with a determined IC50 in the nanomolar order of magnitude. The chemical inhibition of CXCR4 binding sites in exposed cells results in a dramatic reduction of the cytotoxic potency, proving the receptor‐dependent mechanism of cytotoxicity. The insoluble version of T22‐mRTA‐H6 is, contrarily, moderately active, indicating that free, nanostructured protein is the optimal drug form. In animal models of acute myeloid leukemia, T22‐mRTA‐H6 nanoparticles show an impressive and highly selective therapeutic effect, dramatically reducing the leukemia cells affectation of clinically relevant organs. Functionalized T22‐mRTA‐H6 nanoparticles are then promising prototypes of chemically homogeneous, highly potent antitumor nanostructured toxins for precise oncotherapies based on self‐mediated intracellular drug delivery.