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Several examples of nanosized therapeutic and imaging agents have been proposed to date, yet for most of them there is a low chance of clinical translation due to long-term in vivoretention and toxicity risks. The realization of nanoagents that can be removed from the body after use remains thus a great challenge. Here, we demonstrate that nonequilibrium gold–iron alloys behave as shape-morphing nanocrystals with the properties of self-degradable multifunctional nanomedicines. DFT calculations combined with mixing enthalpy-weighted alloying simulations predict that Au–Fe solid solutions can exhibit self-degradation in an aqueous environment if the Fe content exceeds a threshold that depends upon element topology in the nanocrystals. Exploiting a laser-assisted synthesis route, we experimentally confirm that nonequilibrium Au–Fe nanoalloys have a 4D behavior, that is, the ability to change shape, size, and structure over time, becoming ultrasmall Au-rich nanocrystals. In vivotests show the potential of these transformable Au–Fe nanoalloys as efficient multimodal contrast agents for magnetic resonance imaging and computed X-ray absorption tomography and further demonstrate their self-degradation over time, with a significant reduction of long-term accumulation in the body, when compared to benchmark gold or iron oxide contrast agents. Hence, Au–Fe alloy nanoparticles exhibiting 4D behavior can respond to the need for safe and degradable inorganic multifunctional nanomedicines required in clinical translation.

Mechanobiology Hydrogels are biomaterials that recapitulate the physical cues that natural extracellular matrices deliver to cells. In article number 2102276by Giovanna Brusatin and co‐workers, hydrogels' mechanosignaling is monitored by the activation state of YAP/TAZ, revealing distinct checkpoints for cellular mechanosensing: stiffness, adhesiveness and nuclear projected area.

Mechanical signals are pivotal ingredients in how cells perceive and respond to their microenvironments, and to synthetic biomaterials that mimic them. In spite of increasing interest in mechanobiology, probing the effects of physical cues on cell behavior remains challenging for a cell biology laboratory without experience in fabrication of biocompatible materials. Hydrogels are ideal biomaterials recapitulating the physical cues that natural extracellular matrices (ECM) deliver to cells. Here, protocols are streamlined for the synthesis and functionalization of cell adhesive polyacrylamide‐based (PAA‐OH) and fully‐defined polyethyleneglycol‐based (PEG‐RGD) hydrogels tuned at various rigidities for mechanobiology experiments, from 0.3 to >10 kPa.  The mechanosignaling properties of these hydrogels are investigated in distinct cell types by monitoring the activation state of YAP/TAZ. By independently modulating substrate stiffness and adhesiveness, it is found that although ECM stiffness represents an overarching mechanical signal, the density of adhesive sites does impact on cellular mechanosignaling at least at intermediate rigidity values, corresponding to normal and pathological states of living tissues. Using these tools, it is found that YAP/TAZ nuclear accumulation occurs when the projected area of the nucleus surpasses a critical threshold of approximatively 150 µm2. This work suggests the existence of distinct checkpoints for cellular mechanosensing. Mechanosignaling properties of hydrogels are monitored by the activation state of YAP/TAZ. Distinct checkpoints for cellular mechanosensing are revealed: stiffness, an overarching mechanical signal, adhesiveness, and nuclear projected area, which represent critical thresholds for YAP/TAZ activation.

The combination of multiple functions in a single nanoparticle (NP) represents a key advantage of nanomedicine compared to traditional medical approaches. This is well represented by radiotherapy in which the dose of ionizing radiation should be calibrated on sensitizers biodistribution. Ideally, this is possible when the drug acts both as radiation enhancer and imaging contrast agent. Here, an easy, one‐step, laser‐assisted synthetic procedure is used to generate iron–boron (Fe–B) NPs featuring the set of functions required to assist neutron capture therapy (NCT) with magnetic resonance imaging. The Fe–B NPs exceed by three orders of magnitude the payload of boron isotopes contained in clinical sensitizers. The Fe–B NPs have magnetic properties of interest also for magnetophoretic accumulation in tissues and magnetic hyperthermia to assist drug permeation in tissues. Besides, Fe–B NPs are biocompatible and undergo slow degradation in the lysosomal environment that facilitates in vivo clearance through the liver–spleen–kidneys pathway. Overall, the Fe–B NPs represent a new promising tool for future exploitation in magnetic resonance imaging‐guided boron NCT at higher levels of efficacy and tolerability. Iron–boron nanoparticles (NPs) featuring the set of functions required to assist neutron capture therapy with magnetic resonance imaging are obtained by laser synthesis and exceed by three orders of magnitude the payload of boron isotopes contained in clinical sensitizers. These NPs have useful magnetic properties, are biocompatible, and undergo to slow degradation in lysosomal environment.