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Caffeic Acid-Driven Green Synthesis of Rhenium Nanoparticles

Embedded in Self-Templating Double-Shelled ZnMn2O4 Hollow
Microspheres for Ultrasensitive Epinephrine Detection in Biofluids
Rajalakshmi Sakthivel,* Bo-Yuan Chen, Subbiramaniyan Kubendhiran, Lu-Yin Lin,
Sayee Kannan Ramaraj, Yu-Chien Lin, Xinke Liu, Cihun-Siyong Gong,* and Ren-Jei Chung*
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sı Supporting Information

ABSTRACT: In the present work, we report an electrochemical

sensor based on rhenium (Re) nanoparticles embedded within a
double-shelled ZnMn2O4 hollow microsphere (Re@ZnMn2O4) for
ultrasensitive detection of epinephrine (EP) in biofluids. The Re@
ZnMn2O4 material was synthesized via a coprecipitation and
annealing route, followed by a green, caffeic acid (CA)-assisted
chemical reduction. Structural and morphological analyses,
including spectrophotometry, confirmed the high purity, crystal-
linity, and integrity of the material. Electrochemical performance
was evaluated using voltammetry and impedance spectroscopy. The
Re@ZnMn2O4-modified electrode exhibited superior electrochem-
ical activity attributed to its high conductivity, large surface area,
abundant active sites, and efficient charge transfer enabled by the
hollow architecture. EP oxidation followed a diffusion-controlled 2e−/2H+ transfer mechanism. The sensor demonstrated a broad
linear detection range (0.5−1951.3 μM), a low detection limit (0.21 μM), and good sensitivity (0.282 μA μM−1 cm−2).
Furthermore, it showed remarkable reproducibility, long-term stability, and strong resistance to common interferents. Its practical
potential was validated by accurate EP quantification in human serum and urine, highlighting its applicability in clinical diagnostics
and biomedical monitoring.
KEYWORDS: green synthesis, rhenium nanoparticles, double-shell ZnMn2O4, epinephrine sensing, biofluids

E pinephrine ((4-[(1R)-1-hydroxy-2-(methylamino)ethyl]-
benzene-1,2-diol), EP), a vital neurotransmitter and
hormone secreted by the adrenal glands, plays a pivotal role
date, various analytical techniques applied for EP sensing
include liquid chromatography,7 spectrophotometry,8 flow
injection analysis,9 capillary electrophoresis,10 and fluorim-
in regulating cardiovascular function, metabolism, and the etry.11 Nonetheless, these techniques often necessitate intricate
body’s response to stress.1 Alterations in EP levels are and time-intensive sample preparation procedures, leading to
implicated in various pathophysiological conditions, including increased operational costs and extended analysis times.12
adrenal tumors and hypoglycemic unawareness. Additionally, Consequently, bio/chemical sensors have gained significant
EP serves as a critical therapeutic agent in emergency attention in modern analytical chemistry due to their enhanced
medicine, notably in the management of anaphylactic sensitivity, specificity, and potential for real-time, on-site
reactions, cardiac arrest, and septic shock.2 Given the critical analysis.13 Electrochemical sensors have garnered attention
role of EP levels in various physiological processes, there is a due to their simple fabrication, fast response times, high
pressing need for the development of precise sensors capable precision, low cost, compact size, and compatibility,14 making
of accurately quantifying EP concentrations in biofluids.3 them an effective alternative to complex analytical techni-
Under normal conditions, plasma EP concentrations in adults ques.15−18 Unmodified electrodes often exhibit limited
typically remain below 10 ng/L. However, during physical
activity, these levels can increase up to 10-fold, and during
periods of stress, they may rise up to 50-fold or more. This Received: August 17, 2025
significant elevation is attributed to the activation of the Revised: October 28, 2025
sympathetic-adrenal system, which stimulates the adrenal Accepted: November 17, 2025
medulla to release EP into the bloodstream.4,5 Hence, a Published: November 27, 2025
pressing need for the development of precise sensors capable
of accurately quantifying EP concentrations in biofluids.6 To
© 2025 The Authors. Published by
American Chemical Society [Link]
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electron transfer rates and poor conductivity. Therefore, Inspired by the above consideration, in this work, we
modifying them with nanostructured or alternative materials developed a Re@ZnMn2O4 modified electrode to detect EP in
is essential to enhance their electrochemical performance.19 biofluids. The double shell ZnMn2O4 hollow spheres were
Researchers are increasingly focusing on semiconducting synthesized via coprecipitation followed by annealing, while
transition metal oxide materials due to their enhanced the Re@ZnMn2O4 was synthesized using chemical reduction
electrical conductivity, catalytic activity, and electrochemical using CA. The resulting Re@ZnMn2O4 had superior electro-
performance, making them promising candidates for various chemical characteristics toward EP sensing. These character-
applications.20 The AB2O4 spinel structures are mixed-valence istics improve detection efficiency, enable precise target
oxides that exhibit more complex redox processes compared to recognition, and ensure stable performance. The developed
single-component oxides.21 Significantly, spinel zinc manga- sensor provides a broad detection range and a low detection
nate (ZnMn2O4), characterized by divalent zinc occupying limit, making it suitable for real-time clinical monitoring.
tetrahedral sites and trivalent manganese occupying octahedral
sites, exhibits enhanced redox properties. This material is
notably eco-friendly, inexpensive, and nontoxic, making it a
■ EXPERIMENTAL SECTION
Comprehensive details regarding the chemicals, reagents, and
promising candidate for various applications.22,23 Besides, characterization techniques can be found in Sections S1 and S2 of
ZnMn2O4 exhibits superior structural flexibility and enhanced the Supporting Information.
Synthesis of Double-Shell ZnMn2O4 Hollow Spheres. Slight
electrical conductivity, owing to the high mobility of surface modification to the prior report,40 to synthesize ZnMn2O4, 0.2875 g
electrons.24 ZnMn 2O 4 is commonly synthesized using of zinc sulfate heptahydrate (ZnSO4·7H2O), 1.226 g of manganese
coprecipitation methods25 or sol−gel methods,26 followed by sulfate tetrahydrate (MnSO4·4H2O), 1.725 g of sodium tartrate
thermal treatment to achieve the desired phase and dihydrate (Na2C4H4O6·2H2O), and 2.803 g of hexamethylenetetr-
crystallinity. Mukherjee et al. synthesized graphite-sheathed amine (C6H12N4) were dissolved in 50 mL of deionized water and
ZnMn2O4 microspheres via a hydrothermal method for the stirred until fully dissolved. Na2C4H4O6·2H2O acts as a chelating
electrochemical detection of As(III). This approach enhances agent, binding to Zn2+ and Mn2+ ions, stabilizing them in solution and
preventing premature precipitation (step 1). The resulting solution
the charge transport properties of ZnMn2O4, making it a was heated in a water bath at 95 °C for 1.5 h, during which C6H12N4
promising material for electrochemical sensing platforms.24 gradually decomposed (step 2), releasing OH− ions that reacted with
Besides, Li et al. reported using ZnMn2O4 microspheres by the the metal (Zn2+ and Mn2+) ions to form a hydroxide (OH−)
solvothermal method, and it has excellent electrocatalytic precursor (step 3). Following the reaction, the solution was allowed to
activity for H2O2 sensing.27 As a consequence, we have cool naturally to room temperature and was left undisturbed for 15 h.
synthesized double-shell ZnMn2O4 microspheres using the The resulting suspension was vacuum filtered to collect the white
coprecipitation approach. precipitate, which was then thoroughly washed with deionized water
five times to eliminate any remaining ions. The purified precipitate
Introducing transition metals into sensing materials
was dried in a vacuum oven at 60 °C for 12 h. Finally, the dried
effectively enhances the sensitivity and selectivity of electro- hydroxide powder was calcined in a furnace by heating it to 550 °C at
chemical sensors while also speeding up their response and a rate of 2 °C per minute, maintained for 2 h, and then allowed to
recovery times.28 Rhenium (Re) stands out for its unique cool to room temperature, resulting in the formation of spinel
combination of chemical, electronic, and mechanical proper- ZnMn2O4 (step 4).
ties. Its strong resistance to deactivation by sulfur, nitrogen, Step 1: (Dissolution and complex formation)
and phosphorus makes it suitable for use in high-performance ZnSO4 ·7H 2O Zn 2 + + SO4 2 + 7H 2O (1)
areas like aerospace, electronics, cancer treatment, and
electrocatalysis.29 Re-based materials are considered among MnSO4 · 4H 2O Mn 2 + + SO4 2 + 4H 2O (2)
the most promising candidates for versatile catalytic
applications. Beyond their use in pure metallic fles (Re NPs) Na 2C4H4O6 · 2H 2O 2Na + + C4H4O6 2 + 2H 2O (3)
are often employed as catalysts when supported on various
substrates, namely polymers,30 carbon materials,31 DNA Step 2: (Thermal decomposition of HMTA)
scaffolds,32 and γ-Al2O3,33 among others.34 Incorporating Re C6H12N4 + 6H 2O 6HCHO + 4NH3 (4)
NPs into suitable solid supports, as in catalysts,35 enhances not
and
only the support function but also the metal−support interface
chemistry, electronic structure, and catalytic efficiency. Key NH3 + H 2O F NH4+ + OH (5)
features, such as high surface area, fast electron transfer, pore
Step 3: (Precipitation of metal hydroxides)
volume, synergistic effects, and enhanced conductivity,
primarily drive the electrochemical sensing performance.36 Zn 2 + + 2Mn 2 + + OH (from HMTA)
Re NPs initially form in metallic states but tend to oxidize Zn(OH)2 + 2Mn(OH)2 (6)
spontaneously to stabilize their surface. This oxidation,
however, can be managed by the synthesis conditions, choice Step 4: Final step (calcination)
of capping agents, and control of particle size.32 Traditional Zn(OH)2 + 2Mn(OH)2 ZnMn2O4 (spinel) + H 2O (7)
synthesis often relies on many chemicals and causes environ-
mental pollution, while greener methods are attracting interest Synthesis of Re@ZnMn2O4. The Re@ZnMn2O4 material was
but are still not widely studied.37,38 In this work, Re NPs sol prepared through an environmentally friendly synthesis route utilizing
caffeic acid (CA) as a natural reducing agent. To begin, 100 mg of
was synthesized by a green approach using caffeic acid (CA), a
ZnMn2O4 powder was suspended in 22 mL of deionized water and
plant-based antioxidant and strong reducing agent, with stirred magnetically for 30 min to achieve uniform dispersion. In
ammonium perrhenate as the oxidant and CTAB as a shape- parallel, 26.82 mg of ammonium perrhenate (NH4ReO4) was
directing agent.39 The resulting Re@CTA(aq) sol served as a dissolved in 8 mL of deionized water, while 36.44 mg of CTAB
sacrificial seed template for producing Re NPs. was separately dissolved in 5 mL of the same solvent, both under

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Figure 1. Synthesis of ZnMn2O4 and Re@ZnMn2O4 and the construction of the Re@ZnMn2O4 modified GCE to detect EP in human fluids.

Figure 2. (a−b) FESEM images and (c−e) TEM images of ZnMn2O4 at diverse magnifications. (f) HRTEM, (g) SAED pattern, and (h) STEM
image of ZnMn2O4 and the elemental mapping of the (i) ZnMn2O4-mix, (j) Zn, (k) Mn, and (l) O. (m) EDX results of ZnMn2O4.

magnetic stirring until complete dissolution. The NH4ReO4 solution solution, with mixing continued for an additional 15 min to facilitate
was then gradually introduced into the ZnMn2O4 dispersion and interaction among components. Afterward, 9.00 mg of CA was added
stirred for 15 min. This was followed by the addition of the CTAB to the combined solution, and the mixture was stirred at room

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Figure 3. (a−b) FESEM images and (c−e) TEM images of Re@ZnMn2O4 at diverse magnifications. (f) HRTEM and (g) SAED pattern of Re@
ZnMn2O4, and the elemental mapping of the (h) Re@ZnMn2O4-mix, (i) Zn, (j) Mn, (k) O, and (l) Re. (m) EDX results of Re@ZnMn2O4.

temperature for 6 h to allow in situ reduction and deposition of Re of Re0 NPs on their surface to yield the Re0@ZnMn2O4 nano-
nanoparticles on the ZnMn2O4 surface. composite. The overall redox reaction can be represented as
A green chemical reduction approach was employed to synthesize
elemental Re NPs, using the reaction between perrhenate ions Step 4: 2CTA@ReO4(aq) + CA (aq) + ZnMn2O4(s)
(ReO4−) and CA as the reducing agent. The process was carried out
at ambient temperature, with CTAB serving as a stabilizer to control 2Re 0@ZnMn2O4(s) + oxidized CA(quinone)(aq) + 4H 2O
NPs growth and prevent agglomeration. The proposed formation +
+ 2CTA (aq)
mechanism is illustrated below. In the initial step, CTAB dissociates (11)
into CTA+ and Br− ions. Subsequently, the ReO4− ion electrostatically The resulting product was washed through three successive
associates with the CTA+ cation, leading to the formation of a CTA@ centrifugations at 9000 rpm for 10 min each, using alternating rinses
ReO4 complex.39 of deionized water and ethanol (99.8%) to eliminate unreacted
+
Step1: CTAB(aq) F CTA (aq) + Br species. The final solid was dried under vacuum at 60 °C for 12 h,
(8) yielding the desired Re@ZnMn2O4 material, which was stored for
+ electrode fabrication.
Step 2: CTA (aq) + ReO4(aq) F CTA@ReO4(aq) (9) Fabrication of Re@ZnMn2O4 Modified Electrode for EP
− Sensing. The surface of the glassy carbon electrode (GCE) was
Upon introducing CA, ReO4 undergoes a green redox reaction pretreated according to the methods described in the literature.41,42
and is reduced to elemental Re0, while CA is simultaneously oxidized For the fabrication of the Re@ZnMn2O4-modified GCE used in EP
to its corresponding quinone form. sensing, 15 mg of the Re@ZnMn2O4 material was dispersed in 5 mL
of ultrapure water and subjected to ultrasonic treatment for 25 min to
Step 3: 2CTA@ReO4(aq) + CA (aq)
ensure proper homogenization. Subsequently, 6 μL of this suspension
2Re 0@CTA (aq) + oxidized CA(quinone)(aq) + 4H 2O was carefully dropped onto the polished surface of the GCE and dried
at 55 °C for 20 min. Electrochemical characteristics of the Re@
(10) ZnMn2O4 were investigated using CV and EIS techniques. The
Finally, during the reaction, ZnMn2O4 microspheres act as a various concentration of EP was detected by CV and DPV techniques.
supporting substrate, facilitating the in situ formation and deposition The synthesis of ZnMn2O4 and Re@ZnMn2O4 and the construction

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Figure 4. (a) XRD pattern of ZnMn2O4 and Re@ZnMn2O4. (b) XPS survey spectrum of Re@ZnMn2O4 and core-level spectrum of (c) Mn 2p, (d)
Zn 2p, (e) O 1s, and (f) Re 4f. BET analysis of (g) ZnMn2O4 and (h) Re@ZnMn2O4; inset shows BJH plots. (i) EIS analysis of bare GCE,
ZnMn2O4, and Re@ZnMn2O4 modified GCEs.

of the Re@ZnMn2O4 modified GCE to detect EP in human fluids are the ZnMn-hydroxides into well-defined ZnMn2O4 double-
displayed in Figure 1. shelled hollow microspheres. A low-magnification FESEM
Preparation of Biological Samples. According to our earlier image (Figure S2a) shows the ZnMn2O4 material with an
method,43 urine and blood serum samples from healthy donors were
centrifuged at 9000 rpm for 20 min to clear debris. Urine samples (1
increased average size of 2.25 ± 0.25 μm (Figure S2b). This
mL) were diluted to 100 mL and serum samples (2.5 mL) to 25 mL growth in particle size after calcination is attributed to
using 0.1 M PBS at pH 7.0, without additional processing. To test thermally induced phase transformation, particle sintering,
real-sample applicability, varying concentrations of EP (10−50 μM) and grain growth during the formation of the crystalline spinel
were added to the diluted biological fluids. ZnMn2O4 structure.

■ RESULTS AND DISCUSSION

Characterization of ZnMn2O4 and Re@ZnMn2O4. The
Figure 2c−e displays TEM images with varying magnifica-
tions, confirming the double-shelled structure of ZnMn2O4
hollow microspheres. Figure 2f presents an HRTEM image,
structural morphologies of the ZnMn2O4 and Re@ZnMn2O4 where lattice fringes with spacings of 0.246 and 0.49 nm
were characterized via FESEM and TEM techniques. Figure correspond to the (211) and (101) crystal planes of ZnMn2O4,
2a,b presents FESEM images of ZnMn2O4 double-shell hollow respectively. Figure 2g displays the SAED pattern of ZnMn2O4,
microspheres at different magnifications. Initially, solid hollow which aligns well with the XRD results, verifying the successful
microspheres of ZnMn-hydroxides (Figure S1a) were synthe- formation and polycrystalline nature of the ZnMn2O4 phase.
sized via a coprecipitation method, using Na2C4H4O6·2H2O as Elemental composition and distribution of ZnMn2O4 were
a chelating agent and C6H12N4 to gradually release OH− ions. further examined through STEM and elemental mapping, as
The average particle size of the ZnMn-hydroxide precursor was shown in Figure 2h−l. The results illustrate a homogeneous
determined to be 0.97 ± 0.05 μm (Figure S1b) using ImageJ dispersion of zinc (Zn), manganese (Mn), and oxygen (O)
software. Subsequent thermal treatment at 550 °C converted throughout the structure. Additionally, Figure 2m presents the
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Figure 5. (a) CV curves of bare GCE, ZnMn2O4/GCE, and Re@ZnMn2O4/GCE in a 5 mM [Fe(CN)6]3−/4− + 100 mM KCl. (b) CV curves of
increasing scan sweep (υ: 0.01−0.2 V/s) at Re@ZnMn2O4/GCE in 5 mM [Fe(CN)6]3−/4− + 100 mM KCl and the (c) linear plot of υ1/2 against Ipc
and Ipa. (d) CV responses of bare GCE, ZnMn2O4/GCE, and Re@ZnMn2O4/GCE for 100 μM EP detection with (e) corresponding bar chart. (f)
CVs of without EP and increasing concentrations of EP at Re@ZnMn2O4/GCE, and (g) linear plot of EP concentration against current. (h) CV
curves of the diverse pH from 5 to 9 with their current response, and (i) the plot of pH vs Epa and pH vs Ipa.

EDS analysis, revealing that Mn, O, and Zn account for 50.2, Raman spectrum of ZnMn2O4 (Figure S3) displays three
25.8, and 24.0% of the total weight, respectively, supporting well-defined peaks at 639, 365, and 312 cm−1, which are
the desired ZnMn2O4 product formation. indicative of its spinel structure.44 The dominant peak at 639
Figure 3a,b presents FESEM images of Re@ZnMn2O4, cm−1 is attributed to the symmetric stretching vibration of the
confirming successful encapsulation of Re nanoparticles within tetrahedrally coordinated AO4 units, corresponding to the A1g
the double-shelled hollow structure, while maintaining the mode. The additional peaks at 365 and 312 cm−1 arise from
original ZnMn2O4 morphology. Figure 3c−e shows TEM the vibrational modes of oxygen atoms within the octahedral
images of Re@ZnMn2O4, revealing its double-shelled spherical BO6 framework.40 These features confirm the crystalline
ZnMn2O4 spinel phase formation. Additionally, Figure S4
structure, confirming uniform Re nanoparticle distribution on
exhibited the FT-IR spectra of ZnMn2O4 and Re@ZnMn2O4.
the ZnMn2O4 surface. HRTEM data (Figure 3f) indicate
The absorption band at 543 cm−1 is attributed to M-O-M
lattice spacings of 0.271 nm for the (103) plane of ZnMn2O4 stretching vibrations involving both tetrahedral and octahedral
and 0.240 nm for the (100) plane of Re. The SAED pattern in metal−oxygen bonds, while the peak at 612 cm−1 corresponds
Figure 3g aligns with XRD results. Figure 3h−l shows to Mn4+−O2− bond vibrations in tetrahedral sites, both
elemental mapping of Re@ZnMn2O4-mix, Zn, Mn, O, and characteristic of the spinel ZnMn2O4 structure. A distinct
Re, while Figure 3m presents EDS data, with weight band at 979 cm−1 is associated with the C−O stretching
percentages of 44.6% Mn, 24.1% Zn, 22.0% O, and 9.2% Re, vibrations of residual carbonyl groups within the compound.
verifying the composition of the Re@ZnMn2O4 material. Furthermore, the peaks observed at 1105 and 1204 cm−1 are
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assigned to C−O−C asymmetric stretching and O−H bending corresponds to the charge transfer resistance (Rct). At the same
vibrations, respectively, indicating the presence of trace organic time, the low-frequency linear portion specifies diffusion
residues or surface-adsorbed species.45,46 All characteristic control, with Rct reflecting the efficiency of electron transfer
bands of ZnMn2O4 were retained in the Re@ZnMn2O4 at the electrode−electrolyte interface. The measured Rct values
spectrum, along with new peaks at 2855 and 2930 cm−1, were 513 Ω for the bare GCE, 287 Ω for ZnMn2O4/GCE, and
assigned to −CH2− and −N+(CH3)3 vibrations from CTAB. 175 Ω for Re@ZnMn2O4/GCE, as shown in Figure S5. The
Additional signals at 1478, 1581, and 1363 cm−1 correspond to significantly lower Rct observed for Re@ZnMn2O4/GCE
Re0-related species and C−N stretching modes,39,47 confirming indicates improved interfacial conductivity and enhanced
the presence of metallic Re nanoparticles in the composite. electron transport, confirming the effective integration of Re
Figure 4a illustrates the XRD patterns of pristine ZnMn2O4 into the ZnMn2O4 matrix.
and Re@ZnMn2O4. The diffraction peaks appearing at 2θ Cyclic voltammetry (CV) analysis was initially performed to
values of 18.05, 29.28, 31.11, 33.03, 36.50, 37.07, 38.99, 44.75, evaluate the electrochemical performance of both unmodified
50.81, 52.05, 54.94, 56.76, 59.16, 60.90, 65.31, and 75.59° are and modified electrodes using a [Fe(CN)6]3−/4− redox
assigned to the (101), (112), (200), (103), (211), (202), solution at a scan sweep (υ) of 0.05 V/s. Figure 5a illustrates
(004), (220), (204), (105), (312), (303), (321), (224), (400), the electrocatalytic behavior of the blank GCE, ZnMn2O4/
and (413) planes, respectively. These reflections are in strong GCE, and Re@ZnMn2O4/GCE. The bare GCE exhibits a pair
agreement with the standard data from JCPDS card No. 01- of redox peaks with a peak-to-peak separation (ΔEp) of 136
071-2499,40,48 confirming the tetragonal Hetaerolite structure mV and anodic and cathodic peak currents (Ipa and Ipc) of 70
of ZnMn2O4, which crystallizes in the I41/amd space group μA and −67 μA, respectively, resulting in a reversible redox
(No. 141). The diffraction pattern of Re@ZnMn2O4 exhibits a system. In contrast, ZnMn2O4/GCE shows an improved
nearly identical profile to that of unmodified ZnMn2O4, electrochemical response, with a lesser ΔEp of 84 mV and
indicating that the inclusion of Re does not disrupt the original inclined peak currents (Ipa = 75 μA, Ipc = −81 μA), suggesting
crystal framework. A minor peak at 2θ = 26.8°, corresponding enhanced electron transfer relative to the bare electrode.
to the (100) plane of metallic Re (Re0), is also observed.49 Notably, Re@ZnMn2O4/GCE exhibits the best performance
This suggests that Re is integrated into the lattice or surface with a ΔEp of 82 mV and even higher peak currents (Ipa = 85
without forming a separate phase, confirming its successful μA, Ipc = −87 μA), indicating superior electrocatalytic activity
incorporation while preserving the ZnMn2O4 structure. and more efficient electron transfer between the Re@
XPS analysis was conducted to investigate the surface ZnMn2O4/GCE and [Fe(CN)6]3−/4− probe.
composition and valence states in Re@ZnMn2O4. As shown in Figure 5b presents the CV curves of Re@ZnMn2O4/GCE at
Figure 4b, the survey spectrum confirms the presence of Zn, varying scan sweeps (υ = 0.01−0.2 V/s). As the υ increases,
Mn, O, and Re. In Figure 4c, Mn 2p3/2 and 2p1/2 peaks at both Ipa and Ipc are inclined proportionally. Figure 5c shows
639.14/650.81 eV and 640.72/652.28 eV correspond to Mn3+ the linear relationship between Ipa and Ipc versus the υ1/2 (V/
and Mn4+, indicating a mixed-valence state.50 Figure 4d shows s)1/2, confirming a diffusion-controlled redox process at the
Zn 2p3/2 and 2p1/2 peaks at 1019.15 and 1042.17 eV, Re@ZnMn2O4/GCE−electrolyte interface. The regression
consistent with Zn2+.43 In Figure 4e, the O 1s peak at equations are as follows:
527.93 eV (OI) is attributed to lattice oxygen, while the 529.58 1/2
eV (OII) peak suggests adsorbed oxygen species.51 Figure 4f Ipa ( A) = 305.11 (V/s)1/2 + 0.150 (R2 = 0.996)
shows Re 4f7/2 and 4f5/2 peaks at 44.09 and 46.76 eV, (12)
confirming the presence of metallic Re0.49 The XPS results 1/2
verify that Re0 was effectively incorporated into the ZnMn2O4 Ipc ( A) = 328.04 (V/s)1/2 0.302 (R2 = 0.996)
structure. (13)
The textural properties of ZnMn2O4 and Re@ZnMn2O4
The Randles-Sevcik formula was utilized to find the
were investigated through nitrogen adsorption−desorption electroactive surface area (EASA) of bare GCE, ZnMn2O4/
isotherms, as illustrated in Figure 4g,h. Both samples displayed GCE, and Re@ZnMn2O4/GCE, which were measured in a
type IV isotherms with H2 and H3-type hysteresis loops, redox solution.53
indicative of mesoporous characteristics. The BET surface area
of pristine ZnMn2O4 was found to be 36.63 m2/g, whereas the Ip = 2.69 × 105 A C n3/2D1/2 1/2
(14)
Re@ZnMn2O4 exhibited a reduced surface area of 16.22 m2/g.
BJH pore size analysis (insets of Figure 4g,h) revealed average 2
Here, the EASA (cm ), the electron transfer n is (usually 1),
pore diameters of about 21.04 nm for ZnMn2O4 and 23.71 nm the analyte diffusion coefficient is D (7.26 × 10−6 cm2 s−1), υ
for Re@ZnMn2O4. The observed reduction in surface area (0.05 V/s), and the electrolyte concentration is C (5 × 10−6
following Re modification suggests partial pore blockage or mol cm−3). According to the calculation, the EASA is 0.083
encapsulation of Re species within the mesoporous frame- cm2 for bare GCE, 0.090 cm2 for ZnMn2O4/GCE, and 0.102
work.52 Previous reports highlight that mesopores play a cm2 for Re@ZnMn2O4/GCE, suggesting Re@ZnMn2O4/GCE
crucial role in improving electrochemical behavior by offering has a larger active surface area with greater electric
abundant active sites.43 conductivity characteristics.
Electrochemical Characteristics of ZnMn2O4 and Re@ Electrochemical Response of Modified Electrodes
ZnMn2O4. Electrochemical impedance spectroscopy (EIS) with EP Concentrations. The CV curves of bare,
was utilized to examine the interfacial interactions and electron ZnMn2O4, and Re@ZnMn2O4 modified GCEs were measured
transfer behavior between the electrode surface and solution, in a 100 μM EP solution containing 0.1 M PBS at pH 7.0, as
using the [Fe(CN)6]3−/4− redox couple. Figure 4i displays the displayed in Figure 5d. The current response is illustrated in
Nyquist plots for the bare GCE, ZnMn2O4/GCE, and Re@ the bar chart of Figure 5e. The unmodified GCE recorded an
ZnMn2O4/GCE. In these spectra, the semicircular region Ipa of 3.75 μA and Ipc of −2.42 μA, demonstrating quasi-
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Figure 6. (a) CVs obtained with Re@ZnMn2O4/GCE for diverse υ from 0.01 to 0.2 V/s in PBS (pH = 7) containing 100 μM EP and (b) linear
plot of the SQRT υ versus the current. Linear plots of the (c) log υ versus the log Ipa and (d) ln υ versus Epa. (e) The Electrochemical reaction
mechanism of EP.

reversible EP. When modified with ZnMn2O4, the ZnMn2O4/ Ipa( A) = 0.109 C EP ( M) + 0.519; R2 = 0.999 (15)
GCE demonstrated increased redox activity, with Ipa and Ipc
values of 6.65 μA and −4.01 μA, respectively, than bare GCE. Ipc( A) = 0.047 CEP ( M) 3.637; R2 = 0.998 (16)
The Re@ZnMn2O4/GCE exhibited the most pronounced
electrochemical response, achieving an Ipa of 10.41 μA and an The enhanced EP sensing capability of Re@ZnMn2O4
Ipc of −8.39 μA. These results highlight the superior redox provides excellent electrical conductivity, numerous reactive
behavior and enhanced electron transfer capability of the Re- sites, a greater surface area, and high electrocatalytic activity.
doped ZnMn2O4 hybrid. Influence of pH on EP. To investigate the influence of pH
The electroanalytical characteristics and redox response of on the sensing performance of the Re@ZnMn2O4/GCE
Re@ZnMn2O4/GCE were further examined using CV, as toward EP, CV was performed in PBS across a pH range of
presented in Figure 5f. Both the absence of EP and the 5 to 9. As illustrated in Figure 5h, the most pronounced redox
presence of increasing EP concentrations, ranging from 25 to response was observed at pH 7. The optimum pH observed for
175 μM, were tested in a 0.1 M PBS at pH 7.0. As the EP detection was higher than the commonly reported range of
concentration of EP increased, a corresponding rise in redox pH 7−8, and notably above the pH 5 previously used with
peak current was observed, confirming a concentration- cobalt phthalocyanine/single-walled carbon nanotube-based
dependent electrochemical response. This behavior indicates electrodes.54 In aqueous media (pH > 3.0), its oxidation
that the Re@ZnMn2O4/GCE exhibits high sensitivity and follows an ECE mechanism, with each step transferring two
effective electrocatalytic activity for the oxidation and protons and two electrons reversibly.55,56 EP contains hydroxyl
reduction of EP. The variation in peak currents directly groups with pKa values ranging from 8.7 to 12 and an amino
reflects the redox behavior of EP at diverse concentration group with a pKa of approximately 9.9,54 which indicates
levels. Figure 5g presents a linear plot of EP concentration partial ionization in aqueous media and a weakly acidic
against the Ipa and Ipc, along with the regression equations. character. At higher pH values, the hydroxyl groups of EP tend
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Figure 7. (a) DPV response at the Re@ZnMn2O4/GCE on addition of increasing concentrations of EP (0.5−3751 μM). (b) Linear plot of EP
concentration (0.5−1950.3 μM) vs Ipa. (c) DPV curves of the EP response with interferences and the bar chart of (d) current values and (e)
relative error (%). (f) storage stability, and (g) cyclic stability of the EP sensor. Real-time analysis of (h) urine and (i) blood serum samples.

to deprotonate, forming negatively charged −O− species. 100 μM EP solution (Figure 6a). Both Ipa and Ipc rose with
These anionic forms are electrostatically attracted to positively increasing υ, accompanied by minor shifts in peak potentials.
charged regions on the Re@ZnMn2O4/GCE surface, which Lower scan speeds allow a thicker diffusion layer due to
contains Zn2+ and redox-active Re5+/7+ centers. At physio- extended diffusion time, while higher rates restrict diffusion,
logical pH (∼7), this electrostatic interaction enhances EP enhancing analyte transport and current.59 As depicted in
adsorption and detection. Thus, pH 7 was selected for Figure 6b, peak current varies linearly with the SQRT of the υ,
subsequent analysis due to both biological relevance and confirming diffusion-controlled kinetics.60 The regression
optimal sensor response.57 equations are
Figure 5i further demonstrates the variation in oxidation 1/2
current (Ipa) and potential (Epa) as a function of pH, while the Ipa( A) = 57.824 (V/s) 2.946; R2 = 0.997 (18)
Epa shows a linear shift with pH, following the equation:
1/2
Ipc( A) = 33.604 (V/s) 0.846; R2 = 0.999
Epa(V ) = 0.056 pH + 0.785(R2 = 0.988) (17) (19)
The observed slope of 56 mV/pH is close to the theoretical The Re@ZnMn2O4/GCE demonstrates significant affinity
Nernstian value of 59 mV/pH, signifying that the transfer of for EP molecules, likely due to bonding with the hydroxyl
protons and electrons proceeds in equal numbers. Since EP groups present in EP. As shown in Figure 6c, there is a distinct
undergoes a two-electron oxidation, it is inferred that two linear correlation between the log υ and the log Ipa, expressed
protons participate in the reaction as well.58 by the following equations:
Investigation of Scan Rate Influence. The electro-
catalytic behavior and kinetics of the Re@ZnMn2O4/GCE was Log I pa( A) = 0.658 log (V/s) + 1.839; R2 = 0.982
assessed by varying the scan speed from 0.02 to 0.2 V/s in a (20)

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The slope of 0.658 is close to the theoretical value of 0.5,61 Ipa2 ( A) = 0.004 CEP ( M) + 4.965 (R2 = 0.991) (24)
supporting that the oxidation of EP is mainly governed by a
diffusion-controlled mechanism.62 Moreover, the charge trans- The LOD was determined to be 0.21 μM (LOD = 3S/b),20
fer coefficient (α) and electron transfer rate constant (ks) were with the calculated sensitivity of 0.282 μA μM−1 cm−2 for EP
derived from the Laviron equation. According to the Laviron sensing, revealing reliable EP sensing performance throughout
model, such behavior can be described by the linear equation a wide concentration interval. Table 1 highlights the analytical
obtained from a plot of the natural logarithm of υ (ln υ) and
the peak potential (Epa) (Figure 6d). Table 1. Electroanalytical Characteristics of the Re@
ZnMn2O4/GCE Compared with Previous Reports for EP
Epa(V ) = 0.049 ln (V/s) + 0.582; R2 = 0.999 (21) Detection

The obtained slope and intercept values are substituted into electrochemical linear range LOD
electrode material technique (μM) (μM) refs
Laviron’s model.63
PDA@CeO2/GCE DPV 20−100 8.37 5
RT MWCNT/Fe3O4/ DPV 7.5−48 12.3 56
log k s = log(1 ) + (1 )log log Nc/GCE
nF CQDs/CuO/GCE SWV 10−100 15.99 68
(1 )nF Ep MWCNTs/poly- AP 73−1406 22.2 69
FA/GCE
2.303 RT (22)
Gold Nanoporous CV 50−1000 19 66
0 Film
Here, Ep is the anodic peak potential, E represent the formal
GCE-CNF-AuNPs SWV 50−1000 1.7 58
potential, R indicates the gas constant, T is the room
Poly(EBT)-GCE DPV 2.5−50 0.3 70
temperature, α represent the electron transfer coefficient, n
Poly(caffeic acid)- CV 2−80 0.2 71
denotes the charge transfer number, F is the faraday’s constant, GCE
ks represents the electron transfer rate constant of the surface Bare IPGE DPV 0.8−10 0.34 72
process, υ indicates the scan rate, and the E0 could be known as β-CD/NRGO- SWV 4−100 1.12 62
intercept of the calibration plot. Using eq 22, the α and ks ZnFe2O4/Pt
values were determined to be 0.54 and 3.6 × 10−3 s−1, rGO-NiO/ITO SWV 0.5− 50.0 0.423 73
indicating that EP and EPQ are interconverted through a two- NiO-rGO/GCE CV 50−1000 10 74
electron (2e−) transfer process.64 Re@ZnMn2O4/ DPV 0.5−1950.3 0.21 this
Electrooxidation Mechanism of EP. The oxidation GCE work
mechanism of EP in PBS using the Re@ZnMn2O4/GCE is
illustrated in Figure 6e. The CV data demonstrate a quasi- performance of existing electrochemical methods for EP
reversible redox reaction, with a stronger oxidative response detection, showing that the proposed sensor outperforms
compared to the reductive one (Figure 5d,f,h), aligning with previously reported constructed electrodes in terms of
established findings. As indicated in Figure 6a, the process is sensitivity and detection range. Furthermore, its uncomplicated
diffusion-controlled and involves an equal number (1:1) fabrication process contributes to its potential for practical
transfer of electrons and protons. During the forward scan implementation.
from − 0.6 to 0.8 V, EP is oxidized, transforming its hydroxyl Notably, in comparison with previously reported metal
groups into a quinone form (EPQ). On the reverse scan, EPQ oxide-based sensors for EP detection,5,56,62,68,73,74 the Re@
is reduced back to EP at the electrode surface through a 2e−, ZnMn2O4/GCE achieves a wider linear detection range and a
2H+ transfer pathway.65,66 significantly lower LOD. This enhanced performance can be
Electroanalytical Quantification of EP via DPV. The attributed to the material’s excellent electrocatalytic properties,
superior sensing ability of the Re@ZnMn2O4/GCE was including abundant active sites, strong conductivity, and
validated through the quantitative analysis of EP in PBS (pH superior catalytic efficiency. In addition, the Re@ZnMn2O4/
7) using DPV, conducted under optimized electrode and GCE displays consistent response stability, along with excellent
experimental conditions. To generate the calibration curve, precision, making it a promising platform for sensitive and
standard EP solutions were incrementally added into the PBS reliable EP analysis.
electrolyte, and the resulting DPV signals were measured. As Selectivity Assessment. To evaluate the ability of the
illustrated in Figure 7a, well-defined anodic peaks emerged Re@ZnMn2O4/GCE to selectively and specifically detect EP
within the potential range of −0.2 to 0.7 V, with increasing (100 μM), interference experiments were conducted using
peak intensities corresponding to EP concentrations ranging DPV. A range of potential interfering substances, including
from 0.5 to 3751 μM, confirming a clear dependence on small molecules and drugs commonly found in environmental
concentration. Figure 7b presents the corresponding calibra- and biological contexts, was tested. These substances included
tion graph (0.5−1950.3 μM), revealing two distinct linear ascorbic acid (AA), cortisol (CORT), dopamine (DA), ethinyl
segments: Ipa1 at lower concentrations (0.5−275.3 μM) and estradiol (EE2), estradiol (EST), glucose (Glu), hydrogen
Ipa2 at higher concentrations (275.3−1950.3 μM). At low EP peroxide (H2O2), mefenamic acid (MEFA), norepinephrine
concentrations, molecular movement is rapid, leading to a swift (NEP), paracetamol (PA), indomethacin (INDO), and
electrochemical response. In contrast, higher EP concen- serotonin (SER), with each being added in 4-fold. As revealed
trations significantly hinder molecular diffusion, resulting in in Figure 7c, the current responses for each substance were
two distinct linear regions in the calibration curve,67 each is recorded, and the bar chart in Figure 7d summarizes these
described by its respective regression equations: results. The data indicate that the sensor signal remained stable
despite the presence of these substances. Furthermore, Figure
Ipa1 ( A) = 0.02 C EP ( M) + 0.635 (R2 = 0.997) (23) 7e illustrates that the relative error (RE, %) in EP detection
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under interference conditions consistently remained below were confirmed with low RSD values, and reliable detection
6.5%. These findings demonstrate the sensor’s robust was achieved in human urine and serum. This study shows that
selectivity and specificity for EP, even when tested alongside CA-mediated sustainable nanostructures enable sensitive
structurally or chemically similar compounds. biosensing and could be integrated into portable or wearable
Stability (Storage and Cyclic), Reproducibility, and devices for real-time monitoring.
Repeatability. To assess the durability of the EP sensor over
time, a 12-day storage evaluation was conducted. The Re@
ZnMn2O4/GCE was stored at 4 °C and monitored using DPV
■
*
ASSOCIATED CONTENT
sı Supporting Information
measurements, as displayed in Figure 7f. After 12 days, the
sensor preserved 98.0% of its initial current output, with stable The Supporting Information is available free of charge at
peak positions and consistent signal patterns. As depicted in [Link]
Figure S6, the current response showed a slight decrease from Chemicals and reagents; characterization techniques;
3.78 to 3.69 μA, confirming suitability for extended use. In FESEM image and particle size distribution diagram of
addition, Figure 7g displays the cyclic stability of the Re@ ZnMn-hydroxide and ZnMn2O4; Raman spectrum of
ZnMn2O4/GCE. Upon completion of 25 continuous CV ZnMn2O4; FT-IR spectrum of ZnMn2O4 and Re@
scans, the sensor showed minimal signal loss, retaining 99.0% ZnMn2O4; bar chart comparing Rct values for different
of the current, which highlights its excellent stability for EP electrodes; storage stability plot; CV curves for
sensing. reproducibility and repeatability analyses; linear calibra-
To verify the analytical reliability of the constructed EP tion plots for real sample analysis; Table S1. EP levels in
sensor, both reproducibility and repeatability assessments were biological samples (PDF)
performed. Reproducibility was confirmed by modifying six
GCEs with Re@ZnMn2O4 under identical conditions, yielding
consistent CV responses with an RSD of 2.21% (Figure S7a).
Repeatability was assessed through eight consecutive CV scans
■ AUTHOR INFORMATION
Corresponding Authors
on a Re@ZnMn2O4/GCE, showing highly overlapping curves Rajalakshmi Sakthivel − Department of Chemical Engineering
with an RSD of 2.8% (Figure S7b). These findings confirm the and Biotechnology, National Taipei University of Technology
strong measurement precision and dependable performance of (Taipei Tech), Taipei 10608, Taiwan; Email: rajalakshmi@
the Re@ZnMn2O4-based sensor. [Link]
Detection in Actual Samples. The practical utility of the Cihun-Siyong Gong − Department of Electrical Engineering,
Re@ZnMn2O4-modified sensor was assessed by analyzing real National Central University, Zhongli, Taoyuan 320317,
biological samples using DPV, and the results for blank urine Taiwan; [Link]/0000-0001-9414-3798;
and blood serum samples, along with their tested responses, Email: alexgong@[Link]
are shown in Figure 7h,i. First, human urine and serum Ren-Jei Chung − Department of Chemical Engineering and
samples were diluted with 0.1 M PBS, pH 7.0, followed by the Biotechnology, National Taipei University of Technology
addition of EP at varying concentrations (10−50 μM). As (Taipei Tech), Taipei 10608, Taiwan; High-value
illustrated in Figure 7h, the urine sample exhibited a distinct Biomaterials Research and Commercialization Center,
oxidation peak, with the current response increasing propor- National Taipei University of Technology (Taipei Tech),
tionally with EP concentration, and a linear relationship is Taipei 10608, Taiwan; [Link]/0000-0002-0655-
depicted in Figure S8a. A similar trend was observed in the 3680; Phone: (886-2) 2771-2171; Email: rjchung@
serum sample, as presented in Figure 7i, with its linear [Link]
relationship displayed in Figure S8b. The sensor exhibited
consistent recovery and low variability, as illustrated in Table Authors
S1. These findings signify that the Re@ZnMn2O4-based sensor Bo-Yuan Chen − Department of Chemical Engineering and
exhibited robust detection ability even in complex physio- Biotechnology, National Taipei University of Technology
logical samples. (Taipei Tech), Taipei 10608, Taiwan

■ CONCLUSIONS
This work reports the stepwise synthesis of Re@ZnMn2O4
Subbiramaniyan Kubendhiran − Department of Chemical
Engineering and Biotechnology, National Taipei University of
Technology (Taipei Tech), Taipei 10608, Taiwan
hollow microspheres by first preparing self-templated double- Lu-Yin Lin − Department of Chemical Engineering and
shelled ZnMn2O4 hollow microspheres via a coprecipitation Biotechnology, National Taipei University of Technology
and annealing route, followed by Re NPs loading through a (Taipei Tech), Taipei 10608, Taiwan; [Link]/0000-
CA-assisted reduction strategy. The resulting Re@ZnMn2O4 0003-2326-292X
modified GCE exhibits a high electrochemical performance for Sayee Kannan Ramaraj − PG& Research Department of
EP detection. Comprehensive structural and electrochemical Chemistry, Thiagarajar College, Madurai 625009 Tamil
characterization confirmed the formation of a well-defined Nadu, India; [Link]/0000-0001-9761-6132
hollow architecture with enhanced charge transfer and redox Yu-Chien Lin − School of Materials Science and Engineering,
properties. The oxidation of EP followed a diffusion-controlled Nanyang Technological University, Singapore 639798,
mechanism involving a 2e−/2H+ transfer under physiological Singapore; BIOBOND LTD, Corsham, Wiltshire SN13 0B,
pH conditions. The sensor demonstrated a wide linear range U.K.; [Link]/0000-0003-3290-439X
(0.5−1950.3 μM), low LOD (0.21 μM), and good sensitivity Xinke Liu − College of Materials Science and Engineering,
(0.282 μA μM−1 cm−2), along with excellent selectivity (RE < Chinese Engineering and Research Institute of
6.5%) and operational stability (98% signal retention over 12 Microelectronics, Shenzhen University, Shenzhen 518060,
days; 99.0% over 25 cycles). Reproducibility and repeatability China; Department of Electrical and Computer Engineering,
334 [Link]
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ACS Sensors [Link]/acssensors Article

National University of Singapore, Singapore 117583, (11) Guo, Y.; Yang, J.; Wu, X.; Du, A. A Sensitive Fluorimetric
Singapore; [Link]/0000-0002-3472-5945 Method for the Determination of Epinephrine. J. Fluoresc. 2005, 15
(2), 131−136.
Complete contact information is available at: (12) Kiranmai, S.; Kuchi, C.; Sravani, B.; Luczak, T.; Kim, M. J.;
[Link] Madhavi, G.; Veera Manohara Reddy, Y. Construction of Ultra-
sensitive Electrochemical Sensor Using TiO2-Reduced Graphene
Notes Oxide Nanofibers Nanocomposite for Epinephrine Detection. Surf.
The use of human samples was ethically approved (NTU-REC Interfaces 2022, 35, No. 102455.
No.: 202104EM014) and conducted in line with the (13) Yadav, S.; Parihar, A.; Sadique, M. A.; Ranjan, P.; Kumar, N.;
Singhal, A.; Khan, R. Emerging Point-of-Care Optical Biosensing
Declaration of Helsinki. Technologies for Diagnostics of Microbial Infections. ACS Appl. Opt.
The authors declare no competing financial interest. Mater. 2023, 1 (7), 1245−1262.

■ ACKNOWLEDGMENTS
The authors are grateful for the financial support provided by
(14) Li, Z.; Guo, Y.; Yue, H.; Gao, X.; Huang, S.; Zhang, X.; Yu, Y.;
Zhang, H.; Zhang, H. Electrochemical Determination of Epinephrine
Based on Ti3C2Tx MXene-Reduced Graphene Oxide/ITO Elec-
trode. J. Electroanal. Chem. 2021, 895, No. 115425.
the National Science and Technology Council of Taiwan (15) Bindu, A. G.; Bhat, R. S.; Manjunatha, J. G.; Kanthappa, B.
(NSTC 112-2221-E-027-013-MY3; NSTC 114-2221-E-027- Chromium Oxide Nanoparticles as a Modifier of Carbon Paste
070; NSTC 114-2637-E-027-007; 113-2221-E- 008-117-MY3). Electrode for Cyclic Voltametric Assessment of Paracetamol in
Technical assistance from the Precision Analysis and Material Medicinal Sample. Sci. Rep. 2025, 15 (1), No. 6651.
Research Center of the National Taipei University of (16) G, B. A.; Bhat, R. S. Voltammetric Investigation of Synthesized
Technology (Taipei Tech) is appreciated. Zirconium Oxide Nanoparticles for Detection of Catechol. J. Environ.
Chem. Eng. 2025, 13 (3), No. 116046.

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