The treatment of complex diseases such as cancer pathologies requires the simultaneously administration of several drugs in order to improve the effectiveness of the therapy and overwhelm the defensive mechanisms of tumor cells, responsible of the apparition of multidrug resistance (MDR). In this manuscript, a novel nanodevice able to perform remotely controlled release of small molecules and proteins in response to an alternating magnetic field has been presented. This device is based on mesoporous silica nanoparticles with iron oxide nanocrystals encapsulated inside the silica matrix and decorated on the surface with a thermoresponsive copolymer of poly(ethyleneimine)-b-poly(N-isopropylacrylamide) (PEI/ NIPAM). The polymer structure has been designed with a double purpose, to act as temperature-responsive gatekeeper for the drugs trapped inside the silica matrix and, on the other hand, to retain proteins into the polymer shell by electrostatic or hydrogen bonds interactions. The nanocarrier traps the different cargos at low temperatures (20 °C) and releases the retained molecules when the temperature exceeds 35−40 °C following different kinetics. The ability to remotely trigger the release of different therapeutic agents in a controlled manner in response to a nontoxic and highly penetrating external stimulus as alternating magnetic field, along with the synergic effect associated to hyperthermia and chemotherapy, and the possibility to use this nanocarrier as contrast agent in magnetic resonance imagining (MRI) convert this nanodevice in an excellent promising candidate for further studies for oncology therapy.

Magnetically triggered drug delivery nanodevices have attracted great attention in nanomedicine, as they can feature as smart carriers releasing their payload at clinician's will. The key principle of these devices is based on the properties of magnetic cores to generate thermal energy in the presence of an alternating magnetic field. Then, the temperature increase triggers the drug release. Despite this potential, the rapid heat dissipation in living tissues is a serious hindrance for their clinical application. It is hypothesized that magnetic cores could act as hot spots, this is, produce enough heat to trigger the release without the necessity to increase the global temperature. Herein, a nanocarrier has been designed to respond when the temperature reaches the 43ºC. This material has been able to release its payload under an alternating magnetic field without the need of increasing the global temperature of the environment, proving the efficacy of the hot spot mechanism in magnetic-responsive drug delivery devices. INDRODUCTION

In this study, we present an innovation in the tumor treatment in vivo mediated by magnetic mesoporous silica nanoparticles. This device was built with iron oxide magnetic nanoparticles embedded in a mesoporous silica matrix and coated with an engineered thermoresponsive polymer. The magnetic nanoparticles act as internal heating sources under an alternating magnetic field (AMF) that increase the temperature of the surroundings, provoking the polymer transition and consequently the release of a drug trapped inside the silica pores. By a synergic effect between the intracellular hyperthermia and chemotherapy triggered by AMF application, significant tumor growth inhibition was achieved in 48 h after treatment. Furthermore, the small magnetic loading used in the experiments indicates that the treatment is carried out without a global temperature rise of the tissue, which avoids the problem of the necessity to employ large amounts of magnetic cores, as is common in current magnetic hyperthermia.

A novel nanocarrier based on functionalized mesoporous silica nanoparticles able to transport a non-toxic pro-drug and the enzyme responsible for its activation has been presented. This nanodevice is able to generate in situ cytotoxic species once accumulated in the tumoral cell.Enzymes are sensitive macromolecules which can suffer denaturalization in biological media due to the presence of proteases or other aggressive agents. Moreover, the direct attachment of enzymes to the silica surface could reduce their activity by conformational changes or active site blockage. For these reasons, in order to create a robust system able to work in living organisms, the enzymes were previously coated with a protective polymeric shell which allows the attachment on the silica surface preserving their activity. The efficacy of this hybrid nanodevice for antitumoral purposes has been tested against several human tumoral cells as neuroblastoma and leukemia showing significant efficacy. It converts this device in a promising candidate for further in vivo studies for oncology therapy.

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What is the most significant result of this study? The novel ammonia-triggered polymerization of PDA allow us, for the first time, to simultaneously coat mesoporous silica nanoparti-cles and subsequently remove the silica simply through exposition to water,w ithout the need for any harsh chemical reagent to be used. This has allowed us to fabricate an ovel drug delivery nano-carrier with enhanced biocompatibility,while avoiding the accumulation of silica nanoparticles in tissue. What was the inspiration for this cover design? First, to claim the green attractiveness of our PDA coating to remove the silica with water,a se xemplified with aw aterfall landscape. And second, to summarize how this approach is not only green but easy and fully scalable while allowing for the encapsula-tion of aw ide range of drugs and even additional nanoparticles (our treasure). The original idea came from one of the co-authors (F.N ador) and has been made in collaboration with the designer Damaso To rres. What future opportunities do you see (in the light of the results presented in this paper)? The enhanced biocompatibility of the innovative silica-based nano-particles is expected to promote novel opportunities as drug carriers in the treatment of different diseases. For this to become areali-ty,t wo novel experimental challenges must be faced before:i)to study the reproducibility and behaviour of these novel carriers on the translation from in vitro to in vivo experiments and ii)toe x-plore novel ammonia-triggered coatings with other catechol-based systems on the quest for multifunctionality,t argeting, and smart responses to external stimuli. Invited for the cover of this issue is the group of DanielRuiz-Molina at the ICN2 in collaboration with the group of Maria Vallet-Regí at UCM. The image highlightst he green methodology and easy scalability of the method used. Read the full text of the article at

Melanoma is one of the most severe public health issues worldwide, not only because of the high number of cases but also for its poor prognosis in late stages. Therefore, early diagnosis and efficient treatment are key toward a future solution. However, melanoma is highly resistant to cytotoxicity in its metastatic form. In this context, a therapeutic strategy based on a targeted chemo‐photothermal nanotransporter for cytotoxic compounds is proposed. This approach comprises the use of core–multishell gold nanorods, coated with mesoporous silica and further covered with a thermosensitive polymer, which is vectorized for selective internalization in melanoma cells. The proposed nanoformulation is capable of releasing the transported cytotoxic compounds on demand, in response to near‐IR irradiation, with high selectivity and efficacy against malignant cells, even at low concentrations, thereby providing a new tool against melanoma disease.

We report the use of bis-catecholic polymers as candidates for obtaining effective, tunable gatekeeping coatings for mesoporous silica nanoparticles (MSNs) intended for drug release applications. In monomers, catechol rings act as adhesive moieties and reactive sites for polymerization, together with middle linkers which may be chosen to tune the physicochemical properties of the resulting coating. Stable and low-toxicity coatings (pNDGA and pBHZ) were prepared from two bis-catechols of different polarity (NDGA and BHZ) on MSN carriers previously loaded with rhodamine B (RhB) as a model payload, by means of a previously reported synthetic methodology and without any previous surface modification. Coating robustness and payload content were shown to depend significantly on the workup protocol. The release profiles in a model physiological PBS buffer of coated systems (RhB@MSN@pNDGA and RhB@MSN@pBHZ) showed marked differences in the "gatekeeping" behavior of each coating, which correlated qualitatively with the chemical nature of their respective linker moieties. While the uncoated system (RhB@MSN) lost its payload almost completely after 2 days, release from RhB@MSN@pNDGA was virtually negligible, likely due to the low polarity of the parent bis-catechol (NDGA). As opposed to these extremes, RhB@MSN@pBHZ presented the most promising behavior, showing an intermediate release of 50% of the payload in the same period of time.