Atomically Thin Nanoribbons by Exfoliation of Hydrogen-Bonded

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Atomically Thin Nanoribbons by Exfoliation of HydrogenBonded Organic Frameworks for Drug Delivery Xiao-Tong He, Yang-Hui Luo, Dan-Li Hong, Fang-Hui Chen, Zi-Yue Zheng, Cong Wang, Jia-Ying Wang, Chen Chen, and Bai-Wang Sun ACS Appl. Nano Mater., Just Accepted Manuscript • DOI: 10.1021/acsanm.9b00303 • Publication Date (Web): 02 Apr 2019 Downloaded from http://pubs.acs.org on April 3, 2019

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ACS Applied Nano Materials

Atomically Thin Nanoribbons by Exfoliation of Hydrogen-Bonded Organic Frameworks for Drug Delivery

Xiao-Tong He, # Yang-Hui Luo,#, * Dan-Li Hong, Fang-Hui Chen, Zheng ZiYue, Cong Wang, Jia-Ying Wang, Chen Chen, and Bai-Wang Sun*

School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189,

P.R.

China.

E-mail:

[email protected]

(LYH);

[email protected] (SBW). # The

authors are contributed equally.

Keywords: nanoribbon, HOFs, 2D nanomaterials, smart carrier, synergistic therapy effects 1

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Abstract: The currently involved two-dimensional (2D) nanomaterials (2DMs) are referred to as the atomically thin layered materials which are composed of in-plane covalent or coordinated crystalline sheets with different chemical compositions and crystal structures. However, if the crystalline sheets supported by in-plane noncovalent intermolecular interactions, such as hydrogen bonding, van der Waals interactions, etc., can be exfoliated into stable atomically thin nanosheets, then the category and members of 2DMs family will be expanded significantly and extensively. Here we demonstrate that through an ultrasonic force-assisted top-down fabrication technology in the aqueous solution, the three-dimensional (3D) hydrogen-bonded organic frameworks (HOF) TCPP-1,3-DPP, which is composed of one-dimensional (1D) porous ribbons that hold together via robust hydrogen-bonding contacts, can be exfoliated into atomically thin 1D porous nanoribbons (nr-HOF), providing a fine-dispersed stable colloidal suspension with a significant Tyndall effect and ultrahigh surfaces sensitivity. Adding on, the fully exposed surfaces and strong surfaces adsorption ability of nr-HOF accounts for the high loading capacity of Doxo (29.4 %, nr-HOF@Doxo), providing a smart carrier for anticancer drug featuring desired synergistic chemo-PDT-PTT therapy effects that more effective than the commercial Doxo drug, with cell viability as low as 1.3 %. All these results have demonstrated a brand-new 2DMs with appealing properties and applications. 2


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Introduction The last a few decades have witnessed the exponentially growth of interest for two-dimensional (2D) nanomaterials, which will continue to be one of the hottest research topics in the fields of materials science, condensed matter physics, nanotechnology and chemistry.1-8 In general, 2D materials (2DMs) are referred to as the layered structures such as graphene, graphene analogues (h-BN, TMDs, g-C3N4, LDHs, and layered metal oxides), MXenes, MOFs, COFs, black phosphorus, inorganic/organic-inorganic-hybrid perovskites, and so on, which can be exfoliated into the single- or few-layered limitation.9-16 Consequently, ultrahigh surface sensitivity and fully exposed surfaces endow 2DMs with unique and indispensable unprecedented physical, optical, electronic, and chemical properties, as well as various potential promising applications.17-23 One thing should be mentioned is that the currently involved 2DMs are referred to as layered materials that are composed of in-plane covalent or coordinated crystalline sheets with different chemical compositions and crystal structures. Then the questions arise: can the crystalline sheets supported by in-plane noncovalent intermolecular interactions, such as hydrogen bonding, van der Waals interactions, etc., be viewed as 2D materials (2DMs)? And can it be further exfoliated into stable atomically thin nanosheets? If the answers are positive, the category and members of 2DMs family will be expanded significantly and extensively. In addition, the in-plane noncovalent 3



intermolecular interactions would make the 2DMs have unprecedented tunable morphologies and indispensable versatile self-assembly strategies, and would facilitate the fabrication of on-demand materials as well as novel device architectures.24-26 Hence, it would be of significant importance to search for the 2DMs that could be supported by in-plane noncovalent intermolecular interactions.

Scheme 1. Crystal structure of HOF TCPP-1,3-DPP and illustrating of exfoliation of 3D HOF into 1D nanoribbons. To answer the aforementioned questions, the layered-stacked hydrogenbonded organic frameworks (HOFs) can be selected as a potential tester. HOFs are ordered porous materials that are constructed by weak non-covalent intermolecular interactions, which possess the merits of higher solubility, easilyaccessible structural information, more tunable framework behaviors, and ease of regeneration.27-32 However, the development and application of HOFs are still in its early stage owing to the low structural stability, let alone after being exfoliated into stable ultrathin nanosheets. Compared with the classical 2DMs, the layered-stacked HOFs feature in-plane non-covalent contacts, one can only 4


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tailor the organic building blocks judiciously to generate strong in-plane noncovalent contacts, thereby holding the integrity of the nanosheet at the singleor few-layered level. Hence in this work, a three-dimensional (3D) HOF TCPP1,3-DPP (TCPP = meso-tetra(carboxy-phenyl)-porphyrin, 1,3-DPP = 1,3-di(4pyridyl)propane), which was composed of one-dimensional (1D) porous ribbons through on-covalent π…π and C-H…π interactions (Scheme 1),33 has been employed (Figure 1a, Figure S1). Note that, this 3D HOF is highly dynamic with 1D porous ribbons sliding back and forth upon being pressurized and water adsorption in the solid-state under ambient condition. Then the questions arise: what will happen when the 1D porous ribbons sliding forth to achieve complete separation with each other? could the single string of 1D porous ribbon, which was composed of TCPP and 1,3-DPP through the formation of O-H…N hydrogen bonding interactions, have a stable existence after complete separation? If possible, the burgeoning new kinds of 2DMs held by in-plane noncovalent intermolecular interactions can be demonstrated. As we have expected, atomically thin 1D porous nanoribbons (denoted as nr-HOF hereafter) with ultrahigh stability and surfaces sensitivity have been obtained. Indeed, ultrathin 1D nanoribbons of bismuth sulfide (Bi2S3) 34 and gallium oxide (Ga2O3) 35,

which featured with in-chain covenant bond, have been reported, the

atomically thin 1D nanoribbons that hold together by in-chain hydrogen bonding interactions have never been prepared. Adding on, on the one hand, TCPP is the well-known candidate to generate 1O2 and thermal energy upon light 5



irradiation, making nr-HOF the promising material with effective photodynamic

Figure 1. Structural characterizations of exfoliated 1D HOF nanoribbon. (a) Illustrating of the stacking motif of 1D porous nanoribbon (with width of 4.5 nm) in HOF TCPP-1,3-DPP; (b) Photograph of exfoliated 1D nanoribbons dispersed in aqueous solution at 0.2 mg mL−1 concentration with significant Tyndall effect; (c) A typical SEM image, (d) TEM image, (e) selected-area electron diffraction image and (f) AFM image of 1D nanoribbons; (g) The height profile across the nanoribbon indicates a thickness of sub-3.0 nm and lateral width of 100 nm; (h) Comparison between the UV-Vis absorption and (i) Raman 6


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spectroscopy of bulk species and 1D nanoribbons. therapy (PDT) and photothermal therapy (PTT) for cancer, respectively;

36, 37

on the other hand, the fully exposed surfaces and strong surfaces adsorption ability of nr-HOF can serve as smart carriers for anticancer drug doxorubicin (Doxo) with high loading capacity of 29.4 % (denoted as nr-HOF@Doxo hereafter). As a consequence, the promising synergistic chemo-PDT-PTT therapy effects on A549 cells (human lung cancer) have been demonstrated with the merits of considerable biocompatibility and high therapeutic efficacy, demonstrating a brand-new 2DMs with appealing properties and applications.

Results and discussion It should be noted that, the π…π and C-H…π interactions, which hold together the 1D porous ribbons into 3D framework, contribute only 3.6 % and 13.4 % to the total Hirshfeld surfaces of HOF TCPP-1,3-DPP, respectively (Figure S2). As a consequence, the majority of the intermolecular interactions are confined within the 1D ribbons, providing a relative stable 1D species. Thus, it can be expected that the exfoliation of this 3D HOF precursors into single- or fewlayered 1D nanoribbons via a facile top-down strategy that is similar to the exfoliation of traditional 2DMs. By using an ultrasonic force-assisted liquid exfoliation technology in the aqueous solution, for the first time, the atomically thin 1D porous nanoribbons of TCPP-1,3-DPP (nr-HOF) have been obtained, providing a fine-dispersed purple-colored colloidal suspension with a significant Tyndall effect (Figure 1b). 7



Importantly, all of the added 3D precursors (denoted as HOF hereafter) have been exfoliated, giving birth to a stable aqueous colloidal suspension with concentration of 0.2 mg mL-1, the latter can be maintained at least two months without any sedimentation and shown an obviously Tyndall effect exactly as that of the as-prepared (Figure S3a). This phenomenon is indicative of the successful exfoliation of atomically thin 1D HOF nanoribbon with excellent stability in aqueous solution. Note that, the powdered samples of atomically thin 1D nanoribbons were obtained via freeze drying, where the nanoribbon morphology which shows the almost identical appearance with that of bulk HOF, has been observed (Figure 1c), demonstrating the fine re-stacking of 1D porous nanoribbons into the bulk species after solvent removal. This phenomenon has been confirmed by the IR spectroscopy (Figure S4), SEM (scanning electron microscopy) measurements (Figure S5) and elemental analysis (Experimental Section). In addition, the aqueous colloidal suspension has shown identical absorption properties and Raman spectrum with that of bulk species (Figure 1h and 1i), suggesting the preserve of HOF structure at the atomically thin limit. Upon considering the 1D porous strip structures of HOF TCPP-1,3-DPP (Scheme 1), the corresponding 1D nanoribbon species, which were exfoliated from TCPP-1,3-DPP, must be in porous morphology. The thermal gravimetric analysis (TGA) of 1D nanoribbons have shown the similar mass-loss steps as that of bulk precursors (Figure S6), the weight difference of them at the end can be attributed to the absence of lattice water molecules within 1D nanoribbons 8


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species, where, the lattice water molecules that fixed in the interlayer space of bulk precursors have disappeared upon exfoliation, demonstrating the article by article exfoliation mechanism. One thing should be stressed is that this kind of 1D porous nanoribbons can be viewed as a kind of fine-cropped 2D nanosheets, thus a brand-new 2DMs, which was hold by in-plane noncovalent intermolecular interactions, has been demonstrated. Compared with the 1D nanoribbons that hold by in-chain covenant bond, the present species represents the first example of 1D nanoribbons that supported by non-covenant contacts, To further illustrate the successful exfoliation of 1D HOF nanoribbons, the TEM (transmission electron microscopy) and AFM (atom force microscopy) measurements have been performed. In the SEM measurements, the 1D nanoribbons with lateral length of sub-100 nm has been observed (Figure 1d). Interestingly, on the one hand, these 1D nanoribbon structures were composed of atomically thin 1D nanoribbon that are parallel stacked together via weak van der Waals forces (Figure 1d red circles), demonstrating again the highly dynamic characteristic and re-stacking of 1D nanoribbons into the bulk species during the gradual evaporation of the media solvent on the porous TEM grid; on the other hand, the lattice-resolved TEM image indicates the highly crystallinity of these 1D HOF nanoribbons (Figure 1e), demonstrating vividly the high intensity of in-plane noncovalent intermolecular interactions within HOF TCPP-1,3-DPP even down to atomically thin limit. The aforementioned 9



phenomenon was further confirmed by the AFM topological image, where the 1D nanoribbons with lateral area about 100 nm were stacked ordered into barshaped morphology that similar with the bulk species (Figure 1f). What’s more, the height profile of these 1D nanoribbon displayed a thickness of sub-3.0 nm (Figure 1g), demonstrating its atomically thin feature. Upon considering the lateral width of 4.5 nm and vertically stacking of adjacent 1D ribbon structures with half lateral area overlapping in the bulk species, the species in AFM images can be viewed as approximately 20 pieces of 1D nanoribbon single-string in face-to-face arrangements. Thus, we can conclude again that the exfoliation process has resulted in the single string of 1D nanoribbon in aqueous solution, and the single strings can re-arrange in face-to-face manner during the gradual evaporation of the aqueous solvents. To demonstrate the aforementioned article by article exfoliation mechanisms, the TEM and AFM images of the concentrated colloidal suspension have been investigated. Giant nanoribbon/nanosheet species with lateral width in 5001000 nm regions and parallel stacked together via weak van der Waals forces were observed (Figure S7). Note that, on the one hand, a thickness of sub-5.0 nm for each layer has been demonstrated (Figure 2a and 2b), which can be attributed to the horizontal stacking of adjacent 1D nanoribbon single string during concentrate process. On the other hand, deeper exfoliation will damage the regular-shaped morphology of the 1D nanoribbon species (Figure 2c). However, the nanosheet morphologies is still preserved with thickness of sub10


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3.0 nm (Figure 2d), demonstrating again the robust in-plane noncovalent intermolecular interactions between TCPP and 1,3-DPP, despite of its porous feature (Scheme 1). Importantly, the robustness of the present 1D nanoribbons promises its various applications.

Figure 2. Exfoliation of 1D HOF nanoribbon. (a) AFM image of the extend nanoribbons which parallel stacked together via weak van der Waals forces; (b) The height profile across the parallel stacked species, which indicates a thickness of sub-5.0 nm for each layer; (c) AFM image of the deeper exfoliated nanoribbon species; (d) The height profile indicates a thickness of sub-3.0 nm; (e) Photograph of aqueous and (f) solidified species of 1D nanoribbon colloidal suspension. To further illuminate the exfoliation mechanism article by article, SEM images 11



of the exfoliated products obtained by centrifugation under different exfoliation

Figure 3. Loading of Doxo on the 1D HOF porous nanoribbon. Comparison between the UV-Vis absorption (a and b) and fluorescence spectroscopy (c) of Doxo, carriers and loading products, which indicate the high loading capacity of 1D nanoribbons; (d-f) Time-dependent UV/Vis absorption spectroscopy of DPA upon LED light (660 nm) irradiation in the presence of nr-HOF, HOF@Doxo and nr-HOF@Doxo, respectively, which indicate significantly the 12


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superiority of 1D nanoribbon. times have been investigated. As shown in Fig. S8, the article by article exfoliation from the 3D bulk species to single string nanoribbons have been observed vividly. As a consequence, the final stable colloidal suspension was composed of 1D porous nanoribbon single string. This conclusion was indirectly verified by the obviously color change of the colloidal suspension at different conditions. For example, at room temperature, the solution-state is purplecolored (Figure 2e), while upon being cooled to 0 ºC, the frozen-state is greencolored (Figure 2f). This phenomenon significantly demonstrates the atomically thin 1D porous nanoribbon single string featured with ultrahigh surfaces sensitivity to the solvent at various states. Upon considering the metal-free nature and robust atomically thin 1D nanoribbon structure, the present porous nanoribbons of nr-HOF servers as smart carrier for various drug delivery and biological applications thus can be expected. For example, the layered morphology of nanoribbon can act as versatile platform to adsorb drug molecules, and the ultrahigh specific surface area can guarantee the desirable loading capacity. In addition, the narrow size of nanoribbon string promises the desirable bio-distribution. More importantly, TCPP is the well-known candidate to generate singlet oxygen and thermal energy upon light irradiation, that can be used for effective photodynamic therapy (PDT) and photothermal therapy (PTT) for cancer, respectively;

36, 37

The periodic integration of TCPP at the atomically thickness and 2D 13



morphology level will be facilitated to a large extent of the photodynamic / photothermal efficiency. Thus, the combination of nr-HOF with anticancer drugs may represent the promising strategy for the development of synergistic chemo-PDT-PTT therapies. To demonstrate the above-mentioned promising strategy, a proof of concept anticancer drug Doxorubicin (Doxo, Fig. S9) was chosen to load on the present 1D HOF porous nanoribbons. The Doxorubicin hydrochloride in aqueous solution was added dropwise to a stirred aqueous colloidal suspension of nrHOF. After being stirred for 2h, the composite products (denoted as nrHOF@Doxo hereafter) were obtained by centrifugation and washed with water by two times, the loading capacity of Doxo was calculated to be 29.4 % (see the experimental section for details). For comparison, Doxo loading on HOF was also investigated (denoted as HOF@Doxo hereafter), with only 16.5% loading capacity been observed, demonstrating the superiority of present atomically thin nanoribbon for drug loading. The successful loading of Doxo on HOF and nr-HOF was further confirmed by UV/Vis absorption and fluorescence spectroscopy (Figure 3a-3c). The intensity of the spectroscopies shows a linear relationship with the loading capacity, providing a simple but efficient content determination strategy for this kind of drug-carrier composites. Meanwhile, the loading mechanisms can be proposed: the flat methoxy-naphthacene-6,11dione moiety of Doxo can be absorbed on nanoribbon surface, while the hexopyranosyloxy and hydroxyacetyl moieties hang on the surface that can be 14


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utilized for content determination.

Figure 4. Synergistic chemo-PDT-PTT therapy effect. CLSM images of A549 cells incubated with nr-HOF@Doxo for 4h at an equivalent Doxo concentration of 12 μg mL−1 (a), upon irradiation with 660 nm LED light (b) and with combined 660 + 808 nm light (c). In vitro cytotoxicity of Doxo, HOF@ Doxo, nr-HOF@ Doxo, HOF and nr-HOF (d), as well as the synergistic chemo-PDTPTT therapy effect of nr-HOF@ Doxo at various concentrations in A549 cells (e). The promising synergistic chemo-PDT-PTT therapies of nr-HOF@Doxo were verified by MTT experiments. In the experiments, free Doxo drug, HOF@Doxo, nr-HOF@Doxo, HOF and nr-HOF species were all incubated 15



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with A549 cells to evaluate the cooperative therapeutic effects in vitro respectively. Before the MTT evaluation, the singlet oxygen generation (SOG) of the HOF related species was inspected with the help of 9,10diphenylanthracene (DPA). As shown in Figure 3d, upon irradiation with 660 nm OLED light, the UV/Vis absorption spectroscopy of DPA decreased continuously along with time when in the presence of nr-HOF, demonstrating the effective generation of singlet oxygen. It should be noted that, on the one hand, the nr-HOF species have shown higher efficiency than that of bulk HOF (Figure S10), suggesting the superiority of atomically thin nanoribbon for SOG. On the other hand, the loading of Doxo has been detracted to a small extent the SOG efficacy for HOF@Doxo species (Figure 3e). However, no detraction was

observed

for

nr-HOF@Doxo

except

some

delay

(Figure

3f),

demonstrating again the superiority of the atomically thin 1D nanoribbon. Hence, the promising cooperative therapeutic effects with nr-HOF@Doxo species worth looking forward. The efficient cellular uptake of Doxo related therapeutic agents and intracellular release of Doxo into the cytoplasm and nucleus were evaluated by confocal laser scanning microscopy (CLSM) at different incubation times. The intrinsic red fluorescence of Doxo indicates the quick internalization of free Doxo by A549 cells within 4h of incubation, with strong red fluorescence observed in the cytoplasm and nucleic regions (Figure S11. As we have expected, the loading of Doxo on HOF has extended the incubation time to 8h 16


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(Figure S12). However, the loading on nr-HOF has no obvious influence on the cellular uptake and intracellular release of Doxo (Figure 4a and Figure S13), suggesting again the attractive cooperative therapeutic effects within nrHOF@Doxo. Note that, there is no characteristic fluorescence for the nanoribbon carriers to be detected, however, the effective cellular uptake and intracellular release of them can be evaluated by CLSM images upon light irradiation (660 nm). In these measurements, a strong green fluorescence of singlet oxygen full of the A549 cells was observed after 4h of incubation (Figure 4b and Figure S14), demonstrating the synchronously uptake and release of carriers and drug. One thing should be mentioned is that the present HOF will be decomposed into free TCPP and 1,3-DPP under acidic condition, upon considering the slightly acidic environment of cancer cells, the nanoribbon carriers are expected to undergo decomposition upon cellular uptake. This phenomenon was verified by the continuously disappear of 1D nanoribbons during the incubation process (Figure S14), however, the PDT and PTT effects still reserved even after the complete elimination of 1D nanoribbons (Figure S15), which can be attribute to the presence of free TCPP molecules that derived from the decomposition of 1D nanoribbons. Moreover, the efficient uptake and release of carrier can be further evidenced by the PTT effects, as the broken cells have been observed upon near-infrared (NIR) light (808 nm) irradiation (Figure 4c and Figure S15). All these aforementioned results have suggested an almost perfect drug carrier with encouraged cooperative 17



therapeutic effects. The MTT results have confirmed the above prediction. At the concentration of 50 µg mL-1, the carriers themselves have shown slight cytotoxicity with cell viabilities are found to be 83 and 76 % for HOF and nr-HOF species, respectively. Under the same condition, the cell viability for the free Doxo drug is about 8.0 %, demonstrating the outstanding biocompatibility of these two carriers (Figure 4d). Before irradiation, the HOF@Doxo and nr-HOF@Doxo species have shown cell viability about 10.5 and 7.8 %, respectively. Note, the nr-HOF@Doxo species have shown more effective efficacy than the commercial Doxo drug (8.0 % cell survival), demonstrating the highly efficient drug delivery of atomically thin nanoribbon. Upon exposure to the 660 nm light for 10 minutes, the fraction of surviving cells was dropped to about 7.4 and 2.9 %, for HOF@Doxo and nr-HOF@Doxo, respectively (Figure 4e and Figure S15), delivering the effective PDT effects and promising synergistic chemoPDT therapeutic efficacy as expected. More interestingly, further irradiation with 808 nm NIR light for 5 mins have further dropped these two values from 7.4 to 6.6 % and from 2.9 to 1.3 % (Figure 4e and Figure S16), respectively, demonstrating the effective PTT therapy effects under 808 nm irradiation. These results suggesting that, on the one hand, the combined 660 nm and 808 nm irradiation has provided a superior synergistic chemo-PDT-PTT therapy effects than the synergistic chemo-PDT effects under alone 660 nm irradiation; on the other hand, the nr-HOF related species have shown higher therapy 18


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effects than HOF related species for all the conditions, which can be attributed to the superior loading capacity of nr-HOF. Adding on, Doxo is an extensively used anticancer drugs for variously cancer cells, the therapy effects of the present species for A549 human lung cancer cells can also be observed with other cancer cells. Hence, a promising drug delivery system and an effective synergistic chemo-PDT-PTT therapy strategy, with superior therapeutic efficacy based on atomically thin 1D HOF nanoribbon has been demonstrated.

Conclusions In summary, by employing an ultrasonic force-assisted top-down fabrication strategy, for the first time, the atomically thin (sub-3.0 nm) 1D porous nanoribbons assembled by TCPP-based HOF have been successfully prepared and fully characterized. The obtained 1D nanoribbon can be welldistributed in aqueous solution, providing a fine-dispersed stable colloidal suspension with a significant Tyndall effect, as well as ultrahigh surface sensitivity with dramatical color change along with temperatures. More importantly, the presented 1D porous nanoribbon can serve as smart carriers for anticancer drugs for the development of synergistic chemo- PDTPTT effects that more effective than the commercial Doxo drug, which opens an avenue for the development of brand-new 2DMs from HOF materials with appealing properties and applications.

Experimental Section

19



General Considerations. Meso-tetra(carboxy-phenyl)-porphyin (TCPP) and 1,3-di(4-pyrodyl) propane (1,3-DPP) were obtained from MACLIN. Doxorubicin (Doxo.HCl) was purchased from ALADDIN. N, N-Dimethylformamide (DMF, 99.8%) was obtained from BIOSHARP. All the materials were used as received without further purification. Characterization. Roman spectra were monitored by a DXR Raman microscope (DXR 532 nm, Thermo, USA) in the range of 40-4,000 cm-1. Infrared spectra were monitored on a SHIMADZU IR prestige-21 FTIR-8400S spectrometer in the spectral range of 4000-400 cm-1, with the samples in the form of potassium bromide pellets. UV-vis absorption and fluorescence spectrum were recorded at room temperature on Shimadzu UV-2600 doublebeam spectrophotometer and Horiba Flouromax-4 Spectro-fluorometer, respectively. TGA profiles were performed by using a Mettler- Toledo TGA/DSC STARe system at a heating rate of 10 K min-1, under an atmosphere of dry N2 flowing at a rate of 20 cm3 min-1 over a temperature range from 50 to 800 °C. The morphologies of the 1D porous nanoribbons were characterized by using a field emission scanning electron microscope (Hitachi S-4800 20 kV), transmission electron microscope (TEM; Tecnai-G2 20 E-TWIN 200 kV), and AFM (Cypher, Asylum Research). Before these microscopy characterizations, the aqueous suspension of 1D porous nanoribbon was added dropwise onto the holey carbon-coated carbon support copper grids, Si/SiO2, and piranhacleaned Si/SiO2 and then naturally dried. Fluorescent images of A-549 were 20


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carried out on CLSM (Zeiss, Germany). Synthesis of HOF. In a typical procedure, 0.5 mmol (C48H30N4O8, 395 mg) TCPP was dissolved in 16 mL DMF to obtain a brown-colored solution, then it was mixed with an aqueous solution (4 mL) containing 1,3-DPP (C13H14N2, 99 mg, 0.5 mmol) with continuous stirring for 30 min. The mixed solution was then transferred into 25 mL autoclave and heated at 120 °C for 8 h. After that, a deep purple-colored solution was obtained. Slow evaporation of the obtained solution under ambient condition gave birth to violet- colored stripe-like crystals of HOF TCPP-1,3-DPP within one month (yield 82%, based on TCPP). Exfoliation of 1D Nanoribbon (nr-HOF). In a typical experiment, 6 mg of bulk precursors TCPP-1,3-DPP was dispersed in 30 ml deionized water. The mixture was then sonicated in an ultrasonic bath (Brandson, CPX2800H-E, 110 W, 40 KHz) for 30 min and followed by vigorous stirring for 12 h. After that, a milky colloidal suspension was obtained without any sedimentation. The powdered samples of 1D nanoribbons nr-HOF were collected by freeze-drying for further applications. Elemental analysis for the calculated: C, 74.08%; H, 4.84%; N, 8.49%. Found: C, 73.99%; H, 4.75%; N, 8.48%. Preparations of HOF@Doxo. In the typical procedure, 1 mg HOF bulk species and 0.5 mg Doxo·HCl in 5 ml deionized water were stirred continuously at roomtemperature for 24 h under dark condition. Then, the products were collected by centrifugation at 12000 rpm for 10 min, and washed with deionized water until the supernatant was almost colorless. Finally, the products HOF@Doxo 21



were dried by vacuum overnight. Preparations of nr-HOF@Doxo. In the typical procedure, 5 mL colloidal suspension of nr-HOFs (0.2 mg mL-1) and 0.5 mg Doxo·HCl in 0.5 ml deionized water were mixed and stirred continuously at room temperature for 24 h under dark condition. Then, the products were collected by centrifugation at 12000 rpm for 10 min, and washed with deionized water until the supernatant was almost colorless. Finally, the products nr-HOF@Doxo were dried by vacuum for overnight. Doxo Loading Capacities. All the supernatant fractions containing Doxo were collected to detect content values using a standard curve method via UV-vis adsorption spectra. The equation of drug-loading content is listed as follow:

weight of the drug in HOFs DLC(%) = × 100 weight of HOFs Extracellular Singlet Oxygen Detection. 9,10-Diphenylanthracene (DPA) was used for detection of single oxygen generation. HOF-related samples (HOF, nr-HOF, HOF@Doxo, nr-HOF@ Doxo) were dispersed in 30 mL nhexane (c = 0.065 mg mL-1) solution containing DPA (c = 0.48 mg mL-1). The obtained mixtures were then irradiated under a LED (660 nm, 1w) light source for different times. In Vitro Cell Viability. The cell viability of free Doxo drug, HOF@Doxo, nrHOF@Doxo, HOF and nr-HOF were assayed by using standard MTT assay. A549 cells with good vitality were cultivated in 96-well plates at a density of 5103 cells per well, and cultured with RPMI-1640 complete medium in 22


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atmosphere containing 5% CO2 under 37 °C for 24 h. The medium was replaced with the fresh medium containing various concentrations of free Doxo drug, HOF@Doxo, nr-HOF@Doxo, HOF and nr-HOF. After being incubated for 4h, the A549 cells were irradiated with LED light (660 nm,1 w and 880 nm 1 w) for 5 min, respectively. After being incubated for another 20 h, each cell was washed by PBS and the cells were stained with 20 μL of MTT solution (5.0 mg/ml) for 4 h, and 150 μL DMSO was added into each cell subsequently. The plates were shaken for 10 min. Finally, the absorption at 490 nm was measured by using a microplate reader (Thermo Scientific Varioskan Flash, USA). FlowJo software was used for analyzing the results. In Vitro Cellular Uptake. A549 cells were cultured with RPMI-1640 complete medium in the Φ20 mm confocal laser dish at a density of 1×105 cells per dish for 24 h. Subsequently, the medium was replaced with the fresh medium containing 25μg mL-1 free Doxo drug, HOF@Doxo and nr-HOF@Doxo, respectively. After further incubation for different time durations (2 h, 4 h or 8 h), the cells were washed with PBS solution twice and observed by confocal laser scanning microscope (CLSM, Zeiss, Germany). The Doxo signals were recorded at λex = 488 nm. Intracellular ROS Detection. A confocal laser scanning microscopy (CLSM) was used to qualitatively detect the intracellular ROS level. A549 cells were seeded into the Φ20 mm confocal laser dish at a density of 1×105 cells per dish and cultured with RPMI-1640 complete medium at 37 °C for 24 h. The cells 23



were subsequently incubated with HOF@Doxo and nr-HOF@Doxo (25 μg mL1,

1 mL) for 4 h. Cells cultured with medium alone were used as a blank control.

After removing the medium and being washed twice with PBS, DCFH-DA probe (10 μM) was added and then incubated for 30 min at 37 °C. Thereafter, the cells were irradiated with LED light source (660 nm,1 w and 880 nm 1 w) for 5 min and incubated for another 10 min. The cells were washed twice with PBS and the fluorescence images were obtained immediately via CLSM. Data availability. All the data supporting the findings of this study are available within the paper and its Supplementary Information or from the corresponding author upon reasonable request.

Conflicts of interest There are no conflicts to declare.

Acknowledgements This research was supported by the Natural Science Foundation of China (Grant No. 21701023), Natural Science Foundation of Jiangsu Province (Grant No. BK20170660), “Perfect Young Scholars” Program of Southeast University and PAPD of Jiangsu Higher Education Institutions.

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Atomically Thin Nanoribbons by Exfoliation of Hydrogen-Bonded

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