The structural design parameters of a medical microrobot, such as the morphology and surface chemistry, should aim to minimize any physical interactions with the cells of the immune system. However, the same surface-borne design parameters are also critical for the locomotion performance of the microrobots. Understanding the interplay of such parameters targeting high locomotion performance and low immunogenicity at the same time is of paramount importance yet has so far been overlooked. Here, we investigated the interactions of magnetically steerable double-helical microswimmers with mouse macrophage cell lines and splenocytes, freshly harvested from mouse spleens, by systematically changing their helical morphology. We found that the macrophages and splenocytes can recognize and differentially elicit an immune response to helix turn numbers of the microswimmers that otherwise have the same size, bulk physical properties, and surface chemistries. Our findings suggest that the structural optimization of medical microrobots for the locomotion performance and interactions with the immune cells should be considered simultaneously because they are highly entangled and can demand a substantial design compromise from one another. Furthermore, we show that morphology-dependent interactions between macrophages and microswimmers can further present engineering opportunities for biohybrid microrobot designs. We demonstrate immunobots that can combine the steerable mobility of synthetic microswimmers and the immunoregulatory capability of macrophages for potential targeted immunotherapeutic applications.

Nanotoxicology and nanosafety has been a topic of intensive research for about more than 20 years. Nearly 10 000 research papers have been published on the topic, yet there exists a gap in terms of understanding and ways to harmonize nanorisk assessment. In this review, we revisit critically ignored parameters of nanoscale materials (e.g. band gap factor, phase instability and silver leaching problem, defect and instability plasmonic versus inorganic particles) versus their biological counterparts (cell batch-to-batch heterogeneity, biological barrier model design, cellular functional characteristics) which yield variability and nonuniformity in results. We also emphasize system biology approaches to integrate the high throughput screening methods coupled with in vivo and in silico modeling to ensure quality in nanosafety research. We emphasize and highlight the recommendation regarding bridging the mechanistic gaps in fundamental research and predictive biological response in nanotoxicology. The research community has to develop visions to predict the unforeseen problems that do not exist yet in context with nanotoxicity and public health hazards due to the burgeoning use of nanomaterial in consumer's product. ARTICLE HISTORY

Patients with metastatic medullary thyroid cancer (MTC) have limited systemic treatment options. The use of radiolabeled gastrin analogs targeting the cholecystokinin-2 receptor (CCK2R) is an attractive approach. However, their therapeutic efficacy is presumably decreased by their enzymatic degradation in vivo. We aimed to investigate whether the chemically stabilized analog Lu-DOTA-PP-F11N (Lu-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2) performs better than reference analogs with varying in vivo stability, namely Lu-DOTA-MG11 (Lu-DOTA-DGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) and Lu-DOTA-PP-F11 (Lu-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2), and if the use of protease inhibitors further improves CCKR2-targeting. First human data on Lu-DOTA-PP-F11N are also reported. In vitro stability of all analogs was assessed against a panel of extra- and intra-cellular endoproteases, while their in vitro evaluation was performed using the human MTC MZ-CRC-1 and the transfected A431-CCK2R(+) cell lines. Biodistribution without and with the protease inhibitors phosphoramidon (PA) and thiorphan (TO) was assessed 4h post-injection in MZ-CRC-1 and A431-CCK2R(+) dual xenografts. Autoradiography of Lu-DOTA-PP-F11N (without and with PA) and nanoSPECT/CT images were performed. SPECT/CT images ofLu-DOTA-PP-F11N in a metastatic MTC patient were also acquired. natLu-DOTA-PP-F11N is less of a substrate for neprilysines than the other analogs, while intracellular cysteine proteases, like cathepsins-L, might be involved in the degradation of gastrin analogs. The uptake of all radiotracers was higher in MZ-CRC-1 tumors, compared to A431-CCK2R(+), apparently due to the higher number of binding sites on MZ-CRC-1 cells.Lu-DOTA-PP-F11N has the same biodistribution as Lu-DOTA-PP-F11, however, the uptake in the MZ-CRC-1 tumors is almost double (20.7±1.71 vs 11.2±2.94 %IA/g, = 0.0002). Co-administration of PA or TO increases significantly the Lu-DOTA-MG11 uptake in the CCK2R(+) tumors and stomach. Less profound is the effect onLu-DOTA-PP-F11, while no influence or even reduction is observed for Lu-DOTA-PP-F11N (20.7±1.71 vs 15.6±3.80 (with PA) %IA/g, p<0.05 in MZ-CRC-1 tumors). First clinical data show high Lu-DOTA-PP-F11N accumulation in the tumors, stomach, kidneys and colon. The performance of Lu-DOTA-PP-F11N without protease inhibitors is as good as the performance ofLu-DOTA-MG11 in the presence of inhibitors. The human application of single compounds without unessential additives is preferable. Preliminary clinical data spotlight stomach as a potential dose-limiting organ beside the kidneys.

Microcatheters have enabled diverse minimally invasive endovascular operations and notable health benefits compared with open surgeries. However, with tortuous routes far from the arterial puncture site, the distal vascular regions remain challenging for safe catheter access. Therefore, we propose a wireless stent-shaped magnetic soft robot to be deployed, actively navigated, used for medical functions, and retrieved in the example M4 segment of the middle cerebral artery. We investigate shape-adaptively controlled locomotion in phantoms emulating the physiological conditions here, where the lumen diameter shrinks from 1.5 mm to 1 mm, the radius of curvature of the tortuous lumen gets as small as 3 mm, the lumen bifurcation angle goes up to 120°, and the pulsatile flow speed reaches up to 26 cm/s. The robot can also withstand the flow when the magnetic actuation is turned off. These locomotion capabilities are confirmed in porcine arteries ex vivo. Furthermore, variants of the robot could release the tissue plasminogen activator on-demand locally for thrombolysis and function as flow diverters, initiating promising therapies towards acute ischemic stroke, aneurysm, arteriovenous malformation, dural arteriovenous fistulas, and brain tumors. These functions should facilitate the robot’s usage in new distal endovascular operations.

development and implementation of such mobile medical microrobots, including fabrication of soft robotic microdevices, [11,12] synthesis of biocompatible or responsive (adaptive) materials, [13][14][15] and strategies for locomotion inside the body. [16][17][18][19][20][21][22] A myriad of remotely controlled medical microrobots has been proposed to enable shape change, multifunctionality, and reconfiguration in response to different stimuli, such as magnetic fields, [23][24][25][26][27] temperature, [28,29] chemical, [30,31] light, [32] and ultrasound, [33,34] for diverse medical applications, such as target drug delivery, minimally invasive surgery, and remote sensing. [35,36] However, microrobot interaction with biological tissues, complex biofluidic environments, and overlap of multiple stimuli are major challenges toward their future medical applications. [37] The operation of the untethered microrobots is limited in the human body, which is composed of complex physiological environments with a myriad of stimuli, which might trigger non-desired actuation with non-desired function. [38,39] Without decoupled multifunctionality (multifunctional structures), multi-input stimuli of the robot's responsive structures overlap each other, resulting in a partial loss of substantial functional capabilities. [40] In order to avoid the interrupted actuation, decoupling the multiple stimuli inputs is crucial by making each stimulus respond for a single function only. In addition to decoupling multifunctionality, achieving controllable attachment to soft biological tissues is essential for many target implementations, such as collecting bio-signals, applying electrical signals to nerves, and delivering drugs at targeted locations for given durations. [41][42][43][44] However, current designs of micro-scale robots have put more weight on steering and locomotion, so they possess relatively simple surface morphology and lack certain functions, such as tissue attachment ability. [45,46] Inspired by nature, there has been a wide range of biological materials with a variety of morphological structures, which have given us possible solutions to numerous engineering challenges. [47][48][49][50] Among them, pollen grain is emerging as an alternative to adhesive structures for targeted drug delivery applications due to their unique nanospike-like morphology and large inner cavity structure. [51][52][53] Despite the development of pollen graininspired material applications, a majority of the suggested structures have been made from natural pollen grain composed While a majority of wireless microrobots have shown multi-responsiveness to implement complex biomedical functions, their functional executions are strongly dependent on the range of stimulus inputs, which curtails their functional diversity. Furthermore, their responsive functions are coupled to each other, which results in the overlap of the task operations. Here, a 3D-printed multifunctional microrobot inspired by pollen grains with three hydrogel components is demonstrated...