Metal-Phenolic Coordination mediated Nanoemulsions for All-in-One Drug Delivery

doi:10.21203/rs.3.rs-3887134/v1

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Metal-Phenolic Coordination mediated Nanoemulsions for All-in-One Drug Delivery

https://doi.org/10.21203/rs.3.rs-3887134/v1

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Combination chemotherapy is a promising strategy for cancer treatment, enhancing antitumor efficacy while minimizing drug resistance and mitigating the risk of single-drug overdose toxicity. The complexity of pancreatic cancer treatment with its unique avascular and protective stromal barrier, poses challenges in reaching the tumor region – necessitating advanced combination therapy. While polymeric drug delivery carriers for combination chemotherapy have been developed through the synthesis of amphiphilic polymers, this process can be time-consuming and laborious. Polymer entanglement-based drug encapsulation has been limited in achieving high drug encapsulation efficiency because of the intrinsic preference for the localization or encapsulation of drugs based on their polarity. Herein a novel approach was employed, utilizing dynamic bonding and supramolecular assembly at the oil/water interface for drug encapsulation. An emulsion interface was formulated by metal-phenolic coordinate bonds, stabilizing nanoemulsions with diameters ranging from 50 to 100 nm for three weeks. These nanoemulsions co-encapsulated hydrophilic (gemcitabine) and hydrophobic (paclitaxel) anticancer drugs. Moreover, the cellular toxicity of the dual drugs-encapsulated nanoemulsions treatment showed better toxicity (57.0 ± 0.0%) than that of the gemcitabine only-encapsulated (84.0 ± 9.9%) and paclitaxel only-encapsulated (83.4 ± 7.2%) nanoemulsion treatments, demonstrating the potential of multidrug delivery carriers for synergistic combination therapy.

Physical sciences/Materials science/Biomaterials

Physical sciences/Nanoscience and technology/Nanomedicine

Combination chemotherapy involves the administration of a combined multiple therapeutic agents for disease treatment. Two or more types of therapeutic agents have been used to target each therapeutic mechanism or pathway. Combination chemotherapy is also used to reduce cellular drug resistance. Since cancer is closely related to complex tumor biology and progression mechanisms, monotherapy has limited sufficient antitumor efficacy compared with combination chemotherapy^1,2. Accordingly, the US Food and Drug Administration approved 81 new drug combinations for the treatment of hemato-oncology between 2011 and 2021³. The additive or synergistic efficacy of multiple drugs for cancer treatment has been demonstrated by sensitizing or targeting tumors^4–8. In addition, by administering multiple drugs, single-drug overdose-induced toxicity can be avoided, and tumor resistance to drugs in the long term and repeated use of the same drug can be reduced^9–11.

Pancreatic cancer remains a fatal cancer with a poor prognosis due to its avascular structure and strong protective stromal barrier^12–14. Monotherapy has limited anticancer efficacy in the challenging environments. Combination therapy with drug delivery carriers containing multiple drugs is required to overcome insufficient drug delivery efficiency to the pancreas. For example, the anticancer agent gemcitabine (GEM) combined with albumin-bound paclitaxel (nab-paclitaxel) showed a better median survival rate than GEM alone^15–17. It is possible that GEM suppressed tumor stroma and inhibited the expression of cytidine deaminase, a metabolic inactivator of GEM, and nab-paclitaxel-induced oxidative stress in cancer treatment^15,18–20. In another example, GEM combined with polyethylene glycol (PEG)-treated hyaluronidase can overcome resistance to stromal protection, generating chemotherapeutic drugs targeting cancer sites²¹ that are not accessible with a mono-chemotherapeutic agent.

Polymeric drug delivery carriers have also been developed for combination chemotherapy. Researchers have formulated polymeric nanoparticles that can load two or more different drug molecules into compartmented cargo spaces, such as core-shell particles^22,23, Janus structures²⁴, and hydrogel/micelle composites²⁵. The main approach for co-encapsulating multiple drugs is based on the self-assembly nanoparticles or micelles using synthetic amphiphilic polymers via several chemical reactions^7,26,27. This synthetic procedure requires time-consuming and laborious optimization of harmful substances during polymer synthesis and manufacturing^22,27. Improving the co-encapsulation efficiency of hydrophilic and hydrophobic drug molecules in a single cargo space is challenging. This is because drug molecules with different polarities have different preferences for organization and localization within the polymer entanglement space^28,29. To overcome this issue, researchers have attempted to optimize multiple drug encapsulations using appropriate co-solvents, such as a mixture of ethyl acetate and methanol or a mixture of acetone and dichloromethane^30–32; however, the drug loading efficiency remains unsatisfactory.

In recent studies, using host-guest chemistry at the interface of particles, both hydrophilic and hydrophobic drugs have been loaded into a single particle through microfluidic devices^33,34. Hydrophilic and hydrophobic polymers with each functional group at the water-chloroform interface were assembled by cucurbit[8]uril host-guest supramolecular chemistry, formulating microcapsules that can encapsulate hydrophilic and hydrophobic compounds orthogonally³³. Inspired by supramolecular interactions, metal-phenolic coordination at the oil-in-water interface^35,36 was applied to develop particles without microfluidic devices. We developed a new method for preparing nanoemulsions using a dropwise-emulsion process. We proposed a nanoemulsion preparation that reduced the manufacturing time and enabled the simultaneous encapsulation of hydrophilic and hydrophobic compounds within a single drug delivery platform (Fig. 1). Natural phenolics used to prepare nanoemulsions are plant-derived substances that are harmless and biocompatible. Moreover, PEG treatment was applied to the surface of the nanoemulsion to avoid the action of the immune system or stealth-like behavior toward cellular association and to circulate in the body for a longer blood circulation lifetime³⁷. We demonstrated the encapsulation of multiple drugs in a single carrier and conducted an in vitro assessment of the effects of the nanoemulsions on pancreatic cellular uptake. Moreover, cell viability and antitumor efficacy were assessed by treating the nanoemulsions with potential multiple drug carriers.

Preparation and characterization of metal-phenolic coordination mediated nanoemulsions. We considered four phenolic compounds (pyrogallol, GA, EGCG, and TA) (Fig. 1b) in the aqueous phase as candidate molecules that contribute to the formation of an interface in oil-in-water emulsions through coordination with Fe³⁺ (metal ion) in the oil phase (Fig. 1). The interaction of phenolics with Fe³⁺ is strong enough to form nanofilms across the interface of the oil/water biphasic system³⁵ because of the high stability constant of the galloyl groups comprising phenolics with Fe³⁺ complexes³⁸. Pyrogallol and GA have one galloyl group, EGCG has two galloyl groups, and TA has five. Among the phenolic compounds, EGCG and TA formed particle-like colloids in the opaque solution, EGCG-emulsions, and TA-emulsions, respectively (Fig. 2a). In contrast, pyrogallol and GA did not form a particular morphology in the transparent solution (Supplementary Fig. S1). We suggest that phenolics with a certain number of galloyl groups can contribute to the formation of stable emulsions in terms of the degree of coordination bond interactions with metal ions³⁹. With a further ultrasonication step, EGCG-emulsions TA-emulsions had a size of 198 ± 10 and 73 ± 4 nm in diameter and maintained the size values for three weeks (Fig. 2b). The EGCG-emulsions, TA-emulsions had zeta potentials of -12.6 ± 1 mV and − 11.8 ± 0.3 mV, respectively, and comparatively preserved the zeta potential values for three weeks (Fig. 2c). This is because the phenolic hydroxyl groups of EGCG and TA contribute to the anionic charge on the emulsion surface. As we considered nanoemulsions to be utilized as drug delivery carriers with efficient cellular uptake, smaller TA emulsions were chosen for subsequent studies.

To identify whether Fe³⁺-TA coordination mediates nanoemulsion formulation, we performed material combination (Fe³⁺, TA, and Tween 20) experiments to proceed the emulsion process and observed microscopic images of the formulated products (Supplementary Fig. S2). Samples labeled #1 (containing Fe³⁺, TA, and Tween 20) and #2 (containing TA and Tween 20) exhibited colloids, indicating that both TA and Tween 20 are necessary for formulating emulsions. Interestingly, even when Tween 20 was present as a surfactant or stabilizer for the emulsions (#4), the nanoemulsion was not stably formulated. To identify the main contributing molecules for formulating stable nanoemulsions, cryo-TEM images of TA-mediated nanoemulsions with Fe³⁺ (#1) or without Fe³⁺ (#2) were compared after long-term storage, that is, 3 weeks (Fig. 2d and S3a). The #1 solution showed regular spherical particles of 52 ± 10 nm in diameter (Fig. 2d); however, the #2 solution showed unstable nanoemulsions, such as several emulsion droplets inside emulsions (Supplementary Fig. S3a and S3b). In addition, UV-vis absorption spectra of solutions #1 and #2 were compared (Supplementary Fig. S3c). A distinct absorption at approximately 620 nm (characteristic absorption of metal-phenolic coordinate bonds) was observed only in the #1 solution, indicating that metal-phenolic coordinate bonds between Fe³⁺ and TA contributed to the formation of stabilized nanoemulsions. The results indicated that the main molecules contributing to the stability of the nanoemulsions were Fe³⁺ and TA.

To observe how the metal-phenolic coordinate bonds are correlated to the formulated nanoemulsions, the pH-dependent behavior of the nanoemulsions was monitored using microscopic images (Supplementary Fig. S4) and UV-vis absorption spectra (Fig. 2e). The pH of the prepared nanoemulsions in aqueous solution was 3. As shown in Supplementary Fig. S4, the nanoemulsion solution became more transparent as the pH decreased to 1. In contrast, when the pH increased to 12, the nanoemulsion solution became opaque. Microscopic images of the pH-dependent study were noticeable, and the particular colloids were observed under acidic conditions (pH 1, pH 3, and pH 6.5); the colloidal structures disappeared at pH 8, and precipitate forms were observed at pH 12. We suggest that tris-type metal-phenolic coordinate bonds under strong basic conditions are too strong to produce precipitates, rather than stabilizing the interface of the nanoemulsion surface. Under acidic conditions, mono-type and/or bis-type metal-phenolic coordinate bonds are appropriate for formulating nanoemulsions.

The UV-vis absorption spectra of the nanoemulsions were also found to be dependent on pH conditions (Fig. 2e). Some absorption was observed at ~ 610 nm (λ_{abs, max} of mono-complex of metal-phenolic coordinate bonds) at pH 1 and pH 3, absorption occurred at ~ 575 nm (λ_{abs, max} of bis-complex of metal-phenolic coordinate bonds) at pH 7 and pH 8, and ~ 500 nm (λ_{abs, max} of tris-complex of metal-phenolic coordinate bonds) at pH 12^40–45. The coordinate bonds were related to being yellow under acidic conditions, brownish under neutral and purple under basic conditions. The cyclic voltammetry (CV) peaks of the nanoemulsions formed by coordinate bonds were also significantly different from those of the TA aqueous solution (Supplementary Fig. S5). As observed from the CV profiles, both the aqueous TA solution and the nanoemulsions exhibited redox responses with distinct oxidation (700 and 1,800 mV) and reduction (-800 and − 2,000 mV) regions. However, the nanoemulsions exhibited a significantly more pronounced oxidation response, which stems from the different structural motifs that allow TA to be oxidized, promoting weaker Fe³⁺–TA interactions and reducing Fe^{3+ 46,47}. Based on these results, we concluded that the nanoemulsions were mediated and formulated by metal-phenolic coordinate bonds between Fe³⁺ and TA.

Co-encapsulation capacity of nanoemulsions. The dynamic features of host-guest chemistry at the interface of the microcapsule may load hydrophilic and hydrophobic drug molecules³³. To investigate whether the nanoemulsions could encapsulate hydrophilic and hydrophobic compounds, hydrophilic dyes (DAPI: ¹W+, R6G: ²W+) and hydrophobic dyes (Nile red: ¹W-, FITC: ²W-) were used as model drugs. Single encapsulation of a hydrophilic dye (DAPI) and a hydrophobic dye (Nile red) was visualized using optical microscopy (Fig. 3a). In the medical realm of cancer therapy, patients often require multiple drugs with various polarities, accompanied by several injections or repeated administrations. For instance, in pancreatic cancer therapy, both hydrophilic drugs (GEM, 5-fluorouracil, and oxaliplatin) and hydrophobic drugs (PTX and irinotecan) are necessary for patients^4,18,48,49. Consequently, there is a critical need to develop multiple-drug-loadable drug-delivery carriers for combination chemotherapy. As a conceptual demonstration of encapsulating drug combinations within a single drug delivery platform, both a hydrophilic dye (DAPI) and a hydrophobic dye (Nile red) were simultaneously encapsulated in the inner area of the same nanoemulsions, as observed in the merged images (Fig. 3b). Furthermore, triple-type encapsulation of hydrophilic dyes (DAPI and R6G) and hydrophobic dyes (FITC) was demonstrated (Fig. 3c). Fluorescence microscopic images revealed nanoemulsions in which dyes of three different polarities were encapsulated together (all drug loading available in one single carrier; all-in-one drug carriers). Additionally, using chemodrug molecules clinically prescribed for pancreatic cancer, the encapsulation efficiency of the dual hydrophilic drug (GEM) and hydrophobic drug (PTX) were 71.6 ± 3.8% and 42.1 ± 4.9%, respectively. These values are comparable to the encapsulation efficiency observed in the case of single encapsulation of GEM (72.2 ± 1.9%) and PTX (34.3 ± 3.4%) in the nanoemulsions, signifying that the developed nanoemulsion platform is sufficiently versatile for dual drug encapsulation. The stable yet dynamic bonds at the interface are believed to facilitate the co-encapsulation of drugs with different polarities.

Therapeutic efficacy of nanoemulsions as drug delivery carriers. To enhance the utility of the nanoemulsions as drug delivery carriers, PEG was introduced, rendering them PEGylated. This modification aimed to improve colloidal stability and induce a stealth effect in human blood circulation. The stability of the PEGylated nanoemulsions, contingent on the amount of PEG, was investigated over 24 h in two buffers (RPMI and DMEM) commonly used for pancreatic cancer cells (ASPC-1) (Supplementary Fig. S6). A minimum of 200 µL of PEG is required to stabilize the nanoemulsions with the antifouling effect of PEG^50–52. As a demonstration of potential drug delivery carriers using the nanoemulsions, DAPI-encapsulated PEGylated TA-emulsions were treated on ASPC-1 cells. DAPI fluorescence were successfully observed in inside the ASPC-1 cells at all incubation time under the fluorescence microscope. The highest intensity was detected at 4 h of incubation time (Fig. 4a). We further conducted in vitro cytotoxicity assessment of various concentrations (1–1000 nM) of nanoemulsions treated groups. In overall, GP nanoemulsions (GEM and PTX dually encapsulated TA-emulsions) exhibited higher cytotoxicity than single drug encapsulated nanoemulsions (GEM-encapsulated TA-emulsions or PTX-encapsulated TA-emulsions (Fig. 4b) with similar result from dually loadable polymeric drug carriers^53–56. In detail, GP1000 treatment exhibited 57.0 ± 0.0% cell viability, compared with G1000 (84.0 ± 9.9%) and P1000 (83.4 ± 7.2%) treated cell viability. This meant that simultaneous loadable drug delivery carries showed better cytotoxicity on ASPC-1 cells, at least additive toxic effect of two different types of anti-pancreatic cancer drugs, i.e., GEM and PTX.

Metal-phenolic coordinate bonds serve as formulating a versatile multidrug delivery carrier for combination therapy by mediating and forming oil-in-water interface of nanoemulsions through a simple dropwise emulsion process, typically achieved within 5 min. Among the investigated phenolics, TA was identified as suitable for producing colloidally stable nanoemulsions 50 to 100 nm in diameter over three weeks. The contribution of the metal-phenolic coordination bonds to the stabilization of the nanoemulsions was demonstrated by the UV-vis absorption spectra and CV profiles. The nanoemulsions co-encapsulated up to three model drug dyes with different polarities. Additionally, the dual GEM- and PTX-encapsulated nanoemulsions exhibited better cellular toxicity in pancreatic cancer cells than single GEM- or PTX-encapsulated nanoemulsions.

Materials. Tannic acid (TA), anhydrous iron (III) chloride (FeCl₃), and Nile Red were purchased from Thermo Fisher Scientific (Waltham, MA). Pyrogallol, gallic acid (GA), epigallocatechin gallate (EGCG), 4′,6-diamidino-2-phenylindole (DAPI), fluorescein isothiocyanate isomer I (FITC), RPMI-1640 Medium (RPMI) and Dulbecco’s modified Eagle’s medium (DMEM) were purchased from Sigma-Aldrich (St. Louis, MO, USA). Tween 20 and Rhodamine 6G (R6G) were purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). Ethyl acetate (EA) was purchased from Samchun Chemicals (Seoul, Korea). Polyethylene glycol 600 (PEG) was purchased from Daejung Chemicals (Suwon, South Korea). Gemcitabine-HCl (GEM) was obtained from Dong-A ST Co. Ltd. (Seoul, Korea). Paclitaxel (PTX) was purchased from Alfa Aesar (Ward Hill, MA, USA).

Preparation of nanoemulsions. A homogeneous mixture of 0.99 mM FeCl₃ in EA (1 mL) and Tween 20 (0.035 mL) formed the oil phase. The aqueous phase consisted of 13 mM TA dissolved in 2 mL of distilled water (DI water). Using a sterile hypodermic needle (Sterile Hypodermic Needle 22G, Kovax, Seoul, Korea) and a syringe pump (KDS-100CE, KD Scientific, Holliston, MA, USA) under magnetic stirring, 0.4 mL of the oil phase was dropped into 1 mL of the aqueous phase. The drop rate of the syringe pump was set to 45.0 mL/h. After cotton filtration with the prepared opaque solution, the filtrate solution was sonicated (NXP-1002, KODO, Hwaseong, Korea) for 3 min and was filtered with a 0.8 µm syringe filter (ADVANTEC, Tokyo, Japan). To evaporate residual EA, the filtrate solution was placed in a hood with a fan at 24 ± 2°C for 3 h – producing nanoemulsions. Then PEG (0.23 mL) was added to the nanoemulsion solution (1.5 mL), and stirred for 3 h (PEGylated nanoemulsion). The PEGylated nanoemulsion solution was centrifuged (Micro Prime Centrifuge; Centurion Scientific, Chichester, UK) at 15,000 rpm (2,116 × g) for 36 min. The supernatant was removed, and the PEGylated nanoemulsions were redispersed in DI water (1.5 mL).

Characterization of nanoemulsions. The particle sizes and zeta potentials of the nanoemulsion solutions were measured using a Zetasizer (Nano ZS90; Malvern Instruments, Malvern, UK). Images of the nanoemulsions were obtained using optical and fluorescence microscopy (Evos m5000, Thermo Fisher Scientific Inc., Wilmington, DE, USA). The size distribution and morphology were visualized using cryo-TEM (JEM-1400; JEOL Ltd., Tokyo, Japan). The absorption spectra of the nanoemulsions were measured using a UV–vis spectrophotometer (Biochrom Libra S50, Biochrom, Saint Albans, UK). The electrochemical properties of the nanoemulsions were determined using cyclic voltammetry (CV, VersaSTAT 3, AMETEK, Berwyn, PA, USA).

Cryo-TEM analysis of nanoemulsions: Nanoemulsions intended for cryo-TEM analysis were prepared under ambient conditions with a humidity range of 97–99%, utilizing the Vitrobot Mark IV (Thermo Fisher Scientific, Waltham, MA, USA). A volume of 4 µL from the sample solutions was deposited on a lacey-supported grid, followed by the removal of surplus solution using filter paper blotting for 1 s. These grids with the applied solution were then subjected to rapid vitrification through plunge freezing in liquid ethane. The samples were subsequently moved to a Gatan 914 cryo-holder within a Gatan cryo stage (Gatan Inc., Pleasanton, CA, USA), and this setup was then installed on a JEM-1400 microscope functioning at 120 kV. Cryo-TEM images were captured using the XAROSA bottom-mounted CMOS camera (EMSIS GmbH, Münster, Germany), with the subsequent image analysis conducted using RADIUS imaging software (Olympus Soft Imaging Solutions GmbH, Münster, Germany).

Encapsulation of dye and chemotherapeutic agent in nanoemulsions. To encapsulate dyes as drug models or drug molecules in nanoemulsions, hydrophilic dyes (1 mM DAPI and/or R6G) or hydrophilic drugs (1 ppm GEM) were mixed with the aqueous phase, and hydrophobic dyes (1 mM Nile red or FITC) or hydrophobic drugs (1 ppm PTX) were mixed with the oil phase (EA).

The encapsulation efficiencies of GEM and PTX in the nanoemulsions were determined by quantifying the drug amounts in the supernatant using triple quadrupole mass spectrometry (QTrap 6500 Plus, AB SCIEX, Framingham, MA, USA). To prepare samples for injection into HPLC (eluent as a co-solvent of methanol and water), 0.83 mL of methanol was added to 0.5 mL of the supernatant aqueous solution obtained after centrifugation. The encapsulation efficiency was calculated using the following Eq. 5^7,58:

Encapsulation efficiency of drug in nanoemulsion =\(\frac{Amount of initial fed drug- Amount of drug in superanant}{Amount of initial fed drug}\)

In vitro cell tests: Cell culture. The ASPC-1 cell line derived from human pancreatic cancer was provided from ATCC (Manassas, VA, USA) and grown in a humidified incubator at 37°C under 5% CO₂ and 95% air in RPMI medium (Welgene, Gyeongsan-si, Korea) containing 10% fetal bovine serum, 2 mM glutamine, 100 U/mL of penicillin, and 100 µg/mL streptomycin.

Cell viability assay. The viability of ASPC-1 cells was determined using the tetrazolium compound 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) (St. Louis, MO, Sigma-Aldrich). Briefly, ASPC-1 cells were seeded at a density of 5 × 10⁵ cells/2 mL of RPMI media and grown for 24 h in a 37°C incubator. When the cells attained 70–80% confluence, they were allocated into one of following groups; 1) Non-treated (No group), 2) Vehicle treated group (V group), 3) GEM-encapsulated TA-emulsions treated group (G group), 4) PTX-encapsulated TA-emulsions treated group (P group), 5) GEM and PTX dually encapsulated TA-emulsions treated group (GP group). These three treated groups (G, P and GP group) were further classified into four different dosage groups; 1, 10, 100, 1000 nM concentrations of each nanoemulsions. Following incubation for 24 h, the supernatants were discarded, after which 2 mL of fresh RPMI media and 500 µL of MTT solution (2 mg/mL in PBS) were added to each well. The cells were then incubated at 37°C for 4 h, after which the formazan precipitate was dissolved in dimethyl sulfoxide (DMSO, Duchefa Biochemie, Haarlem, Netherlands), and the absorbance was read at 570 nm directly in the wells using a Vmax plate reader (San Jose, CA, Molecular Devices).

DAPI stained cell images. The morphological changes in apoptotic cells were observed by fluorescent microscopy after DAPI staining. Briefly, ASPC-1 cells were seeded at a density of 5 × 10⁵ cells/2 mL in 6-well plates, they were grown to 70–80% confluence in a 37°C incubator. After washing once with 1× PBS, cells were incubated with PEGylated TA-emulsions for another four different time (2, 4, 13 and 30 h), then fixed in 4% formaldehyde (Junsei Chemical Co. Ltd., Tokyo, Japan) for 1 h and permeated with 0.1% Triton X-100 (Biosesang Inc., Seongnam, Korea) for 5 min. Next, the DNA-specific fluorochrome DAPI (100 µM, Invitrogen Co., Ltd., Carlsbad, CA, USA) was applied to each well, after which samples were incubated for 10 min in the dark at room temperature. Finally, the cells were washed three times with 1× PBS and examined using a fluorescent microscope (Evos m5000, Thermo Fisher Scientific Inc., Wilmington, DE, USA) at 200× magnification.

Acknowledgments

This work was supported by the Technology Development Program (S3364028) funded by the Ministry of SMEs and Startups (MSS, Korea), a National Research Foundation of Korea (NRF) grant funded by the Korean government, MSIP (Ministry of Science, ICT & Future Planning) (NRF-2021R1F1A105923711), and the BK21 FOUR Program through the NRF funded by the Ministry of Education, Korea (F21YY8109033).

Author contributions

S.S. proposed the research concept; Y.J., J.W.P., and S.J.L. conducted the experiments; Y.J. prepared fgures; A.S., Y.K., S.G.C., E.L., S.M.W., Y.-H.K., and D.Y.H. analyzed, interpreted the data and wrote the manuscript; S.S. revised the manuscript.

Competing interests

The authors declare no competing interests.

Data Availability.

All data supporting this study and its findings are available within the article and its Supplementary Information. Any data deemed relevant are available from the corresponding author upon request.

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No competing interests reported.

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Metal-Phenolic Coordination mediated Nanoemulsions for All-in-One Drug Delivery

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