This is the accepted version of the journal article: Yang, Yunhui; Arqué, Xavier; Patiño, Tania; [et al.]. «Enzyme-Powered Porous Micromotors Built from a Hierarchical Micro- And Mesoporous UiO-Type Metal- Organic Framework». Journal of the American Chemical Society, Vol. 142, Num. 50 (2020), p. 20962-20967. DOI 10.1021/jacs.0c11061 This version is available at https://ddd.uab.cat/record/275377 under the terms of the license Enzyme-powered porous micromotors built from a hierarchical micro- and mesoporous UiO-type metal-organic framework Yunhui Yang,# Xavier Arqué,# Tania Patiño,* Vincent Guillerm, Pascal-Raphael Blersch, Javier Pérez-Carvajal, Inhar Imaz,* Daniel Maspoch,* Samuel Sánchez* Supporting information for this article is given via a link at the end of the document ABSTRACT: Here, we report the design, synthesis and functional testing of enzyme-powered porous micromotors built from a metal-organic framework (MOF). We began by subjecting a pre-synthesized microporous UiO-type MOF to ozo- nolysis, to confer it with mesopores sufficiently large to adsorb and host the enzyme catalase (size: 6-10 nm). We then encapsulated catalase inside the mesopores, observing that they are hosted in those mesopores located at the subsurface of the MOF crystals. In the presence of H2O2 fuel, MOF motors (or MOFtors) exhibit jet-like propulsion enabled by enzymatic generation of oxygen bubbles. Moreover, thanks to their hierarchical pore system, the MOFtors retain sufficient free space for adsorption of additional targeted species, which we validated by testing a MOFtor for removal of Rhodamine B during self-propulsion. The field of bio-inspired micro- and nanomotors has pores large enough (mesopores) to adsorb and host en- evolved extensively so many synthetic structures have been zymes. For instance, the groups of Farha,37 Zhou38 and Ma39 reported over the past decade.1 From the various ways exploited MOFs mesopores to encapsulate various en- these tiny motors can be powered, self-propulsion via zymes. Importantly, for a MOF to be used as the chassis of chemical reactions is one of the most widely used being an enzyme-powered porous motor, it must combine mes- natural catalysts, such as enzymes, a promising alternative opores sufficiently large to host the enzyme used for pro- to achieve efficient and biocompatible systems. Several pulsion, with micropores of an appropriate size to adsorb milestones towards real-world applications of such motors and release additional guest species. have been achieved, primarily in the fields of biomedicine2- Herein we report the design of an enzyme-powered, po- 7 and environmental applications.8-11 In those applications, rous, MOF-based micromotor via compartmentalized en- porosity of the motor chassis is crucial as it enables adsorp- capsulation of the enzyme catalase within a hierarchical tion, transport and/or release of cargo (e.g. drugs or pollu- micro- and mesoporous MOF (Figure 1a). We chose cata- tants),8,12,13 being its performance dictated mainly by its lase as a model enzyme, as it has been extensively used to sorption-capacity and its cargo transport-versatility.14-17 induce ballistic propulsion through bubble propulsion via Among the alternatives available for developing enzyme- decomposition of H2O2.40-43 Moreover, we selected an UiO- powered porous motors, metal-organic frameworks type Zr-MOF as the chassis because of its well-known wa- (MOFs) are an attractive choice.18,19 MOFs exhibit very high ter stability;44 a condition that should fulfil any MOF in- surface areas, tunable pore sizes and shapes, and adjusta- tended to be used for the fabrication of motors powered by ble pore-surface functionality, suggesting their potential enzymatic reactions. In this design, another essential con- for myriad applications, including gas-storage, separation, dition was the use of a UiO-type MOF with mesopores suf- catalysis, contaminant removal, and drug delivery.20,21 In ficiently large to host catalase (size: 6-10 nm) and mi- fact, researchers have used MOFs to build stable and cropores that preserve the ability to adsorb and/or release adaptable chassis for micro- and nanomotors,18,22 in which additional guest species. In order to rationally design this motion is based on Marangoni effects,23–26 magnetically- driven corkscrew locomotion27,28 or bubble propulsion.29-35 In parallel, researchers have demonstrated that biomole- cules — particularly, enzymes — can be encapsulated within MOFs for protection and to confer the MOFs with new functionalities, mainly in catalysis. For instance, Fal- caro, Doonan and co-workers explored biomimetic miner- alization and controlled co-precipitation to encapsulate several enzymes in ZIF-8.36 Another challenging approach has required custom-made linkers to assemble MOFs with Figure 1. a) Schematic representation of the multi-step process used to synthesize the MOFtors. Cross sections of the crystals at bottom. b) FESEM image of ozonated Zr-fcu-azo/sti-30%. Scale bar: 10 µm. c,d) PXRD and N2 isotherms of Zr-fcu-azo/sti- 30% before (red) and after (blue) ozonolysis, and after catalase encapsulation (orange). In c, simulated pattern for Zr-fcu-azo (black). e) Encapsulation efficiency (blue) and oxygen generated (orange) vs. time. MOF, we decided to use an approach that we had devel- initial non-ozonated samples (Figured 1b,c). The ozonated oped earlier, whereby we subject pre-synthesized mi- Zr-fcu-azo/sti-30% was analyzed by 1H-NMR, which re- croporous MOFs functionalized with a mixture of linkers vealed that these linkers had been completely removed that do or do not contain olefins to ozonolysis, which se- from the crystals (Figure S4). The creation of mesopores lectively oxidizes the olefins to generate new meso- was confirmed by N2 sorption tests at 77 K (Figures 1d and pores.45,46 To do so, we subjected a pre-synthesized UiO- S6,7). The isotherm did not show the type-I shape of the type MOF to this ozonolysis process, and then exploited isotherm of the starting MOF: instead, it exhibited a small the newly-formed mesopores to host the catalase mole- hysteresis between the adsorption and desorption branch, cules. characteristic of mesoporosity. As expected, ozonolysis re- We began with the synthesis of a UiO-type Zr-fcu-MOF duced the apparent SBET down to 2470 m2/g. However, this (hereafter called Zr-fcu-azo/sti-30%), formed by mixing decrease was offset by the creation of mesopores, at a pro- 4,4’-azobenzenedicarboxylic acid (H2azo) with olefin-con- portion of 24%.47 taining 4,4’-stilbenedicarboxylic acid (H2sti) linkers at a Once we had confirmed the formation of Zr-fcu-MOF molar ratio of 7:3, respectively. Field-Emission Scanning containing hierarchical porosity, we proceeded to study Electron Microscopy (FESEM) revealed the formation of the adsorption of catalase into the latter. For this, 5 mg of octahedral microcrystals (size: 2-15 µm) characteristic of ozonated Zr-fcu-azo/sti-30% were incubated in 1 mL of an Zr-fcu-MOFs (Figure S3), and powder X-ray diffraction aqueous solution of catalase (3 mg/mL) for different peri- (PXRD; Figure 1c) confirmed the phase purity. Proton nu- ods of time. After each period, the amount of encapsulated clear magnetic resonance (1H-NMR) of digested crystals catalase was quantified by the standard Bradford protein confirmed the formation of Zr-fcu-azo/sti-30% in an assay. The amount of catalase confined in the ozonated Zr- azo/sti molar ratio of 7:3 (Figure S4). Moreover, N2 sorption fcu-azo/sti-30% was gradually increased from 1 h (0.14± analysis (77 K) confirmed the microporosity of Zr-fcu- 0.01 mg catalase/mg MOF) to 8 h (0.21± 0.01 mg cata- azo/sti-30%, with a Brunauer-Emmett-Teller surface area lase/mg MOF) (Figure 1e). To further demonstrate the en- (SBET) of 2830 m2/g (Figures 1d and S5). capsulation of catalase into the mesopores, we used confo- Next, we selectively removed the sti linkers and residual cal laser scanning microscopy (CLSM) to study the spatial Zr(IV) fragments in Zr-fcu-azo/sti-30% by our ozonolysis distribution of catalase within the Zr-fcu-azo/sti-30% crys- protocol,45,46 and washing the ozonated solid with 0.5 M tals. For this, we repeated the encapsulation process over 8 solution of acetic acid in DMF. The ozonated Zr-fcu- h, using a catalase tagged with the green dye fluorescein azo/sti-30% particles did not exhibit any marked difference isothiocyanate (FITC). For comparison, we also repeated in their octahedral shape and crystallinity compared to the this encapsulation process using a non-ozonated Zr-fcu- (Figure 1e). These results are consistent with those of the aforementioned motion experiments. We have tentatively attributed this slight decrease in activity and motion to ei- ther a certain degree of inactivation of catalase inside the MOF crystals, or to the fact that the catalase molecules dif- fuse into the interior of MOF crystals more at longer incu- bation times, thereby complicating both arrival of the H2O2 molecules to the enzymes as well as release of the O2 bub- bles produced by the enzymatic reaction. Once we had confirmed the optimum incubation time of 1 h, we further investigated the motion capabilities of the Figure 2. CLSM micrographs of a) as-synthesized and corresponding MOFtor. Initially, we studied the influence b) ozonated Zr-fcu-azo/sti-30% crystals after incuba- of the surfactant, by reproducing the recording of MOFtors tion with FITC-tagged catalase (green) for 8 h. Scale in an aqueous solution containing 0.5% H2O2 in the pres- bars: 50 µm (a,b); 5 µm (inset,a) and 3 µm (inset,b). ence and absence of Triton X-100 (Figure 3b,c). Figure 3c shows different snapshots from the video recordings with azo/sti-30%, which does not contain mesopores. Micro- their corresponding trajectories where MOFtors in a Triton graphs of the ozonated and the non-ozonated Zr-fcu- X-100 dilution displayed high bubble-production, leading azo/sti-30% demonstrated that catalase is encapsulated to propulsion (Video S2). However, in the absence of sur- only within the crystals of the former, where it is predom- factant (Figure 3c), we did not observe any bubbles or self- inantly compartmentalized at the subsurface (Figures propulsion. We reasoned that the surfactant in the me- 2a,b). We attributed the preferential localization of cata- dium reduced the surface tension of the liquid, which in lase at the subsurface of each MOF crystal to the initial ran- turn promoted formation of and stabilized the bubbles.40,55 dom distribution of azo- and sti- linkers that, following re- We also assessed the self-propulsion of the MOFtor as a moval of the latter via ozonolysis, produce crystals in function of H2O2 concentration (Figure 3b). We observed which the meso- and micropores are randomly localized. self-propulsion at low surfactant and fuel concentrations56 This makes the external mesoscale cavities more accessible compared to those in other studies, in which 3% to 5% for catalase than the internal ones, as the diffusion of cata- H2O2 was utilized.53 Given its toxicity, minimizing the con- lase into the internal large cavities is highly restricted by the probability of encountering pores smaller than the size of catalase. We next studied the self-propulsion of Zr-fcu-azo/sti- 30% crystals into which we had incorporated catalase (hereafter called MOFtors) for 1, 3, 5 or 8 h. For these ex- periments, we considered that bubble-propulsion is im- proved by the addition of surfactants to the media;48-52 thus, we recorded the MOFtor crystals in an aqueous solu- tion containing 0.5% H2O2 and Triton X-100 at a 0.25% (v/v) concentration. Remarkably, all four samples showed bubble generation and motion capability (Figure 3a), pro- pelling themselves by a thrust of oxygen bubbles released asymmetrically from a point of nucleation (Video S1). In this regard, researchers have reported that any cavity in a micromotor structure -in this case in the MOF crystal-, due to porosity, surface-defects or crystal-aggregation, can en- able accumulation of oxygen bubbles for jet-like propul- sion.53,54 Among the MOFtors generated at different incubation times, the one corresponding to 1 h incubation reached the highest maximum speed (2.79 ± 0.55 body-lengths/s). In- terestingly, incubation time was indirectly proportional to speed (Figure 3a). To explore this trend, we quantified the enzymatic activity (O2 production) of the catalase confined inside the MOFtors, using the displacement method. For Figure 3. a) Speed of MOFtors obtained at different in- all samples, the amount of generated O2 increased during cubation times. b) Speed of the MOFtors at different the first 2 min, and then gradually plateaued at a saturation H2O2 concentrations. c) Snapshots of the trajectories of value (Figure S11). The MOFtor from 1 h of incubation gen- MOFtors at different times in the presence (bottom) or erated the greatest amount of O2 (61.1 μmol/mgMOFtor) and absence (top) of 0.25% Triton X-100. highest speed of O2-generation ([49 μmol O2/s]/mgMOFtor) centration of the H2O2 is important for biological and en- the versatility of MOFs as the structural basis of enzyme- powered porous motors for delivery, sorption and catalytic applications. ASSOCIATED CONTENT The Supporting Information is available free of charge via the Internet at http://pubs.acs.org. Supporting Information: Chemicals, instrumenta- Figure 4. CLSM micrographs of MOFtors after adsorp- tion, synthetic procedures, FESEM, XRPD, porosity tion of Rhodamine B (red). In b), the left image is the data, and videos showing MOFtor movement. (PDF) superposition of both right images showing adsorbed Rhodamine B (red, top) and compartmentalized FITC- Video S1: Representative MOFtor bubble self-propul- tagged catalase (green, bottom). Scale bars: 50 µm (a) sion for different catalase incubation times. (AVI) and 5 µm (b). Video S2: Representative MOFtor bubble self-pro- vironmental applications. When we increased the H2O2 pulsion with and without surfactant. (AVI) concentration to 1.5%, the self-propulsion increased, reaching a maximum speed of 3.56 ± 0.56 body-lengths/s Video S3: Representative MOFtor bubble self-pro- and propelling for 7.0 ± 0.4 min (Video S3). Yet, motion can pulsion for different H2O2 concentrations. (AVI) be resumed after addition of fresh fuel. Given that our MOFtor combines both meso- and mi- AUTHOR INFORMATION cropores, and that the catalase enzymes are encapsulated mainly in the mesopores located at the crystal sub-surface, Corresponding Authors we envisioned using the remaining empty pores to adsorb Tania Patiño - Institute for Bioengineering of Catalonia other guest molecules. To this end, N2-sorption measure- (IBEC), The Barcelona Institute of Science and Technol- ments confirmed that MOFtors has accessible porosity, ogy (BIST), Baldiri i Reixac 10-12, 08028 Barcelona, with an SBET of 1715 m2/g, and that their mesopore propor- Spain; Chemistry Department, University of Rome, Tor tion is 20%. We also studied the capacity of MOFtors to Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy; capture Rhodamine B, a common water pollutant from the E-mail: tpatino@ibecbarcelona.eu textile, plastic and dye industries, during self-propulsion in water. To this end, catalase-powered MOFtors (5 mg) were Inhar Imaz - Catalan Institute of Nanoscience and Nano- dispersed in an aqueous solution (1 mL) of 0.5 mg/mL Rho- technology (ICN2), CSIC and Barcelona Institute of Sci- ence and Technology, Campus UAB, Bellaterra, 08193 damine B and 1.5% H2O2/0.25 % Triton X-100 at room tem- Barcelona, Spain; E-mail: inhar.imaz@icn2.cat perature. After 5 min of incubation, the Rhodamine B con- tent adsorbed by the MOFtors was determined by UV-Vis Daniel Maspoch - Catalan Institute of Nanoscience and spectrometry. We observed that they had captured 51.0 ± Nanotechnology (ICN2), CSIC and Barcelona Institute of 2.7 % % of Rhodamine B from the solution. For compari- Science and Technology, Campus UAB, Bellaterra, 08193 son, without using H2O2/Triton X-100, non-powered Barcelona, Spain; ICREA, Pg. Lluís Companys 23, Barce- MOFtors adsorbed only 14.6 ± 6.4 % of Rhodamine B, thus lona, 08010, Spain; E-mail: daniel.maspoch@icn2.cat confirming the positive effect of self-propulsion in the per- Samuel Sánchez - Institute for Bioengineering of Catalonia formance of MOFtors. Adsorption of Rhodamine B in the (IBEC), The Barcelona Institute of Science and Technol- catalase-powered MOFtors was also confirmed by CLSM. ogy (BIST), Baldiri i Reixac 10-12, 08028 Barcelona, Indeed, Figure 4 shows that, while catalase remains local- Spain; ICREA, Pg. Lluís Companys 23, Barcelona, 08010, ized at the sub-surface of the crystals, Rhodamine B mole- Spain; E-mail: ssanchez@ibecbarcelona.eu cules are adsorbed throughout the entire crystal. In conclusion, we have reported the multi-step synthesis Authors of enzyme-powered MOF-based porous motors, which in- Yunhui Yang - Catalan Institute of Nanoscience and Nano- volves generating new mesopores in a microporous UiO- technology (ICN2), CSIC and Barcelona Institute of Sci- 66-type MOF, via ozonolysis. We exploited the newly-gen- ence and Technology, Campus UAB, Bellaterra, 08193 erated mesopores to adsorb and host the enzyme catalase, Barcelona, Spain. which were compartmentalized at the subsurface of each Xavier Arqué - Institute for Bioengineering of Catalonia MOF crystal. This encapsulation enabled jet-like bubble (IBEC), The Barcelona Institute of Science and Technol- propulsion of the MOF crystals using H2O2 as fuel, even at ogy (BIST), Baldiri i Reixac 10-12, 08028 Barcelona, very low concentrations. Moreover, the remaining unoccu- Spain. pied micro- and mesopores in these MOFtors can be used for adsorbing additional species, as we demonstrated with Vincent Guillerm - Catalan Institute of Nanoscience and capture of Rhodamine B in water. Our work demonstrates Nanotechnology (ICN2), CSIC and Barcelona Institute of Science and Technology, Campus UAB, Bellaterra, 08193 L.; Gaitzsch, J.; Fullstone, G.; Tian, X.; Azizi, J.; Preston, J.; Barcelona, Spain. Volpe, G.; Battaglia, G. Chemotactic Synthetic Vesicles: De- sign and Applications in Blood-Brain Barrier Crossing. Sci. Present address: Functional Materials Design, Discovery Adv. 2017, 3 (8), e1700362. 3 and Development Research Group (FMD ), Advanced (6) Wang, J.; Toebes, B. J.; Plachokova, A. S.; Liu, Q.; Deng, D.; Membranes and Porous Materials Center (AMPM), Divi- Jansen, J. A.; Yang, F.; Wilson, D. A. Self-Propelled PLGA Mi- sion of Physical Sciences and Engineering (PSE), King cromotor with Chemotactic Response to Inflammation. Adv. Healthc. Mater. 2020, 1901710, 1–8. Abdullah University of Science and Technology (7) Wu, Y.; Lin, X.; Wu, Z.; Möhwald, H.; He, Q. Self-Propelled (KAUST), Thuwal 23955-6900, Saudi Arabia. Polymer Multilayer Janus Capsules for Effective Drug Deliv- Pascal Blersch - Institute for Bioengineering of Catalonia ery and Light-Triggered Release. ACS Appl. Mater. Interfaces 2014, 6 (13), 10476–10481. (IBEC), The Barcelona Institute of Science and Technol- (8) Parmar, J.; Vilela, D.; Villa, K.; Wang, J.; Sánchez, S. Micro- ogy (BIST), Baldiri i Reixac 10-12, 08028 Barcelona, and Nanomotors as Active Environmental Microcleaners Spain. and Sensors. J. Am. Chem. Soc. 2018, 140 (30), 9317–9331. (9) Guix, M.; Orozco, J.; Gracía, M.; Gao, W.; Sattayasamitsathit, Javier Pérez-Carvajal - Catalan Institute of Nanoscience S.; Merkoçi, A.; Escarpa, A.; Wang, J. Superhydrophobic Al- and Nanotechnology (ICN2), CSIC and Barcelona Insti- kanethiol-Coated Microsubmarines for Effective Removal of tute of Science and Technology, Campus UAB, Bel- Oil. ACS Nano 2012, 6 (5), 4445–4451. laterra, 08193 Barcelona, Spain. (10) Gao, W.; Wang, J. The Environmental Impact of Micro / Na- nomachines : A Review. ACS Nano 2014, 8 (4), 3170–3180. Present address: Laboratoire de Physique de l’Ecole Nor- (11) Orozco, J.; García-Gradilla, V.; D’Agostino, M.; Gao, W.; Cor- male Supérieure, ENS, Université PSL, CNRS, Sorbonne tés, A.; Wang, J. Artificial Enzyme-Powered Microfish for Université, 45, rue Ulm, 75005, Paris, France. Water-Quality Testing. ACS Nano 2013, 7 (1), 818–824. (12) Medina-Sánchez, M.; Xu, H.; Schmidt, O. G. Micro- and Authors Contributions Nano-Motors: The New Generation of Drug Carriers. Ther. Deliv. 2018, 9 (4), 303–316. # Y.Y. and X.A.: These authors contributed equally to this (13) Eskandarloo, H.; Kierulf, A.; Abbaspourrad, A. Nano- and work. Micromotors for Cleaning Polluted Waters: Focused Review on Pollutant Removal Mechanisms. Nanoscale 2017, 9 (37), ACKNOWLEDGMENT 13850–13863. (14) Llopis-Lorente, A.; Garciá-Fernández, A.; Murillo-Cremaes, This work was supported by BIST-IGNITE (MOFtors), the N.; Hortelaõ, A. C.; Patinõ, T.; Villalonga, R.; Sancenón, F.; Spanish MINECO (project RTI2018-095622-B-I00), the Cata- Martínez-Máñez, R.; Sánchez, S. Enzyme-Powered Gated lan AGAUR (project 2017 SGR 238), and the European Re- Mesoporous Silica Nanomotors for on-Command Intracellu- search Council (ERC) under the European Union’s Horizon lar Payload Delivery. ACS Nano 2019, 13 (10), 12171–12183. 2020 research and innovation programme (grant agreement (15) Hortelão, A. C.; Patiño, T.; Perez-Jiménez, A.; Blanco, À.; Sánchez, S. Enzyme-Powered Nanobots Enhance Anticancer No 866348: iNanoSwarms). It was also funded by the CERCA Drug Delivery. Adv. Funct. Mater. 2017, 28 (25), 1–10. Program/Generalitat de Catalunya. ICN2 is supported by the (16) Wu, Y.; Lin, X.; Wu, Z.; Möhwald, H.; He, Q. Self-Propelled Severo Ochoa program from the Spanish MINECO (Grant No. Polymer Multilayer Janus Capsules for Effective Drug Deliv- SEV-2017-0706). Y.Y. acknowledges the China Scholarship ery and Light-Triggered Release. ACS Appl. Mater. Interfaces Council for scholarship support. X.A. thanks the Spanish 2014, 6 (13), 10476–10481. MINECO for the Severo Ochoa program (SEV-2014-0425) for (17) Llopis-Lorente, A.; García-Fernández, A.; Lucena-Sánchez, the PhD fellowship (PRE2018-083712). S.S.thanks the Peng- E.; Díez, P.; Sancenón, F.; Villalonga, R.; Wilson, D. A.; Mar- cheng Scholar Professorship at Harbin Institute of Technology tínez-Máñez, R. Stimulus-Responsive Nanomotors Based on Gated Enzyme-Powered Janus Au-Mesoporous Silica Nano- Shenzhen, China. T.P. thanks the European Union’s Horizon particles for Enhanced Cargo Delivery. Chem. Commun. 2020 research and innovation program, under the Marie 2019, 55 (87), 13164–13167. Skłodowska-Curie Individual Fellowship (H2020-MSCA- (18) Terzopoulou, A.; Nicholas, J. D.; Chen, X.-Z.; Nelson, B. J.; IF2018, DNA-bots). Pané, J.; Puigmartí-Luis, J. Metal-Organic Frameworks in Motion. Chem. Rev. 2020, 120 (20), 11175–11193. 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