Descriptor-Guided Design of High-Efficiency Narrowband Phosphorescent Probes for Bioimaging

Abstract

Organic room-temperature phosphorescence (ORTP) with narrow emission bands is highly attractive for high-contrast biomedical imaging. However, most ORTP systems suffer from low efficiency due to weak spin–orbit coupling, and their emission spectra are often broadened by strong electron-vibration coupling. Herein, we propose a descriptor-guided design framework to achieve efficient and narrowband ORTP through intramolecular noncovalent conformational locks (NoCLs). Two fundamental descriptors are established to link structure to photophysical properties: the NoCL strength S, a rigidity metric that governs electron-vibration coupling and dictates spectral bandwidth, and the orbital character γ, which controls intersystem crossing and determines triplet-state abundance. Using these descriptors, we design a series of benzophenone derivatives bearing NoCL and identify the 2SOBr system, which exhibits the highest phosphorescence efficiency of 58.22% among the explored narrowband ORTP emitters, with a full width at half maximum 36 nm under ambient conditions. As a biological probe, 2SOBr enables lysosome-specific cellular imaging with high signal-to-noise ratios of 15.93, outperforming commercial green fluorescent probes (<10). This work establishes a quantitative structure-descriptor-property relationship that provides a strategy for the design of efficient narrowband organic phosphorescent materials and expands their potential for high-contrast optical imaging.

Introduction

Luminescent probes are essential for advancing modern biomedical imaging, enabling real-time visualization of cellular and tissue processes with high spatial resolution. − Due to their broad spectral features, their performance, however, is often compromised by the intrinsic autofluorescence of biological samples. , In multicolor imaging, this overlap with probe emission causes channel crosstalk and significantly reduces signal-to-noise ratios (SNRs <10 for commercial green fluorescent probes). − To address these limitations, the development of probes with both high brightness and narrowband emission is crucial for achieving high-contrast and reliable bioimaging performance. Organic room-temperature phosphorescence (ORTP) materials have attracted growing attention as a potential strategy to overcome the limitations of conventional fluorescent probes. − Their long-lived triplet emission enables temporal separation from autofluorescence, offering a direct means to enhance imaging contrast. , Moreover, their structural diversity and metal-free composition make them attractive candidates for biological applications. , Yet, several intrinsic challenges remain. Triplet excitons exhibit weak spin–orbit coupling (ξ) with singlet excitons and are prone to quenching by oxygen, leading to reduced emission efficiency in physiological environments; − and at the same time, their strong electron-vibration couplings (EVC) produce broadened emission spectra with low color purity. , Consequently, most ORTP afterglow materials still exhibit broad emission bands, with full width at half maximum (FWHM) typically exceeding 50 nm and in many cases nearing 100 nm. , These photophysical constraints fundamentally limit the utility of current ORTP materials for precise bioimaging.

Recently, many strategies, such as the introduction of multiple-resonance frameworks, rigid scaffolds, enhancing low-frequency vibronic bands, and phosphorescence-mediated Förster resonance energy transfer, where long-lived triplet excitons are transferred from a phosphorescent donor to a narrowband fluorescent acceptor that dictates the final emission bandwidth, have been undertaken in the literature. These have successfully demonstrated spectrally narrow phosphorescence or afterglow emission in the solid state. However, an overlooked limitation emerges across these systems: narrowband phosphorescence is generally realized in rigid host matrices, whereas it vanishes in dilute solution. This phenomenon reflects the intrinsic fragility of organic triplet excitons, their nonradiative decay arising from active intramolecular motions and conformational disorder in non-restrictive environments. A recent study reported narrowband ORTP even in solution, which was enabled by an intrinsically large phosphorescence rate constant and minimal structural reorganization. However, such cases remain rare, and a molecular design strategy that simultaneously ensures narrow emission bandwidth and high phosphorescence efficiency under ambient conditions is still lacking. More importantly, the fundamental relationships between molecular structure, FWHM, and excited-state dynamics remain insufficiently understood. − This suggests that a subtle interplay among multiple photophysical factors governs RTP performance. Therefore, a theoretically guided framework is essential for the rational design of ORTP materials that combine narrowband emission with high efficiency, thereby enabling their practical application in high-contrast biomedical imaging.

Herein, we investigate a series of benzophenone-based derivatives for ORTP, leveraging the intrinsic n→π* character of the carbonyl group that facilitates intersystem crossing (ISC). On this basis, a descriptor-guided structure-strength-property relationship is established: (i) an intramolecular noncovalent conformational locks (NoCLs) descriptor, which effectively captures both the suppressed low-frequency torsional motions and the high-frequency carbonyl vibrations leading to weakened EVC; and (ii) an orbital character descriptor, which measures the ISC efficiency and triplet population. These descriptors establish a clear link between molecular conformation and electronic structure to both emission bandwidth and phosphorescence efficiency. As a representative example, the 2SOBr system exhibits narrowband phosphorescence with an FWHM of 36 nm (1157 cm^–1) and a high phosphorescence quantum yield (Φ _P) of 58.22% in the PMMA matrix. In cellular imaging experiments, 2SOBr shows preferential accumulation in lysosomes when co-cultured with HeLa cells, yielding a high co-localization coefficient of 98.01% and a high SNR of 15.93. This work demonstrates the effectiveness of descriptor-guided conformational control in a series of heteroaromatic 1,2-diketone derivatives in producing efficient, narrowband phosphorescent probes for high-contrast bioimaging.

Results and Discussion

Designing ORTP materials that combine a narrow emission spectrum with high phosphorescence efficiency remains challenging. According to the fundamental Franck-Condon (FC) principle, molecular emission spectra are broadened by the EVC, in contrast to the line spectra of atoms. The spectral width is therefore determined by the strength of EVCs (quantified as the reorganization energy λ) and their distribution across vibrational normal modes. The λ _i of a normal mode can be calculated as ${\lambda }_{\mathrm{i}}=\frac{1}{2}{\omega }_i^2\mathrm{\Delta }{Q}_i^2$ , in which ω _i is the vibrational frequency and ΔQ _i represents the displacement between the molecular equilibrium geometries in the ground and excited states. In our previous work, the NoCL strength descriptor (S, S = (−cosα)·cos²θ·(1-e ^d‑dv )²) was defined based on geometric parameters and showed a strong inverse correlation with λ. As illustrated in Figure a, the benzophenone derivative features two aromatic wings flanking the central dicarbonyl moiety, wherein each five-membered ring maintains coplanarity with its neighboring carbonyl group via π-conjugation. The parameter θ is defined as the dihedral angle between these two conjugated planes, which quantitatively describes the torsional distortion of the molecular backbone. d and dv represent the actual distance between sulfur and oxygen atoms and the sum of van der Waals radii of sulfur and oxygen atoms in the S···O interaction, respectively, and α denotes the angle between the S···O interaction and the S–C bond. Here, although two symmetric S···O NoCLs exist, only one NoCL is marked in Figure a. Hence, the S can serve as a useful descriptor for designing ORTP materials with a small FWHM value. In parallel, phosphorescence is the emission from the first triplet state (T₁), which is populated primarily through ISC from the singlet manifold rather than through direct optical absorption, and ORTP efficiency critically depends on the efficiency of the ISC processes. In our previous work, the orbital character descriptor (γ, γ = α ^S·β ^T + β ^S·α ^T) was proposed to quantify the orbital compatibility between singlet and triplet excited states. The singlet/triplet excited state can be regarded as an admixture of n→π* and π→π* configurations with portions α and β (Figure a), which has been proposed to characterize the ISC rate constant and RTP efficiency. A largerγ value correlates with higher RTP in organic materials, and this descriptor has been successfully applied in the design of high-performance ORTP materials. Thus, these descriptors S and γ establish a descriptor-guided framework that links molecular conformation and electronic structure to the spectral bandwidth and efficiency of ORTP. Here, these molecular design principles are further exploited in a series of heteroaromatic 1,2-diketone derivatives, as illustrated in Figure b. Benzophenone derivatives were selected as the molecular platform because of intrinsic CO moieties, which provide n orbitals essential for ISC and are widely employed in ORTP materials. However, the rotational flexibility introduced by single-bond connections in benzophenone leads to large-amplitude torsional motions and pronounced EVC. To address this limitation, heteroatoms (S and O) were incorporated to induce NoCLs, thereby stabilizing planar conformations and enhancing structural rigidity. Furthermore, Br substitution was introduced to modulate molecular composition and enhance ξ, thereby offering an additional handle to optimize the ISC process.

1.

(A) Descriptor-guided framework and molecular design strategy of narrowband ORTP. The dihedral angle (θ) describes the relative twist between the two conjugated planes defined by the thiophene ring and the carbonyl group, which are individually planar. (b) Nine molecular structures of 2OOBr­(Cl), 3SOBr­(Cl), 2SOBr­(Cl), 2OO, 3SO, and 2SO.

More in detail, we designed three model compounds2OOBr, 3SOBr, and 2SOBrto investigate the descriptor-guided effect on phosphorescence (Figure b). Among them, 2OOBr contains no NoCL, whereas 3SOBr and 2SOBr incorporate H···O and S···O NoCLs, respectively. The equilibrium geometries of these compounds were optimized in the ground state (S₀) at the M06-2X­(D3)/6-31+G­(d) level. − All optimized structures were confirmed to be local minima by normal-mode analysis with no imaginary frequencies. For each compound, two plausible conformations were considered and optimized; the most stable conformation was identified by comparing their energies (Table S1), and the resulting equilibrium structures are shown in Figure a. The dihedral angle between the five-membered ring and the carbonyl group gradually decreased from 56.09° (2OOBr) to 43.60° (3SOBr) and 0.02° (2SOBr), indicating a transition from a twisted to a nearly planar configuration. The short H···O (2.39 Å) and S···O (2.69 Å) contacts in 3SOBr and 2SOBr, which are notably shorter than the corresponding van der Waals radii sums (2.72 and 3.32 Å, respectively), provide direct geometric evidence for the formation of NoCLs. Consistently, the NoCL strength descriptors S for 2OOBr, 3SOBr, and 2SOBr are determined to be 0.004, 0.08, and 0.75 based on the geometries in the S₀ state, respectively. Similar trends are observed for the S₁ and T₁ states, with the corresponding S values summarized in Table S2. These results demonstrate that stronger NoCLs effectively enhance conformational planarity, laying the structural basis for suppressing EVC and narrowing the phosphorescence bandwidth.

2.

(A) Parameters (distances and dihedral angles) and values of NoCL descriptors obtained based on optimized structures in the S₀. (b) Natural bond orbital (NBO) overlap between the n-orbitals and the σ*-orbitals and QTAIM distributions. The (3, −1) bond critical points (BCPs) and (3, +1) ring critical points (RCPs) were marked in orange dots. (c, d) S versus the reorganization energies (λ) and full width at half maximum (FWHM) of 2OOBr, 3SOBr, and 2SOBr.

To further investigate the existence and strength of the NoCLs, natural bond orbital (NBO) and noncovalent interaction (NCI) analyses were performed. As shown in Figure b, there is negligible overlap between the nonbonding lone pair orbital of the carbonyl oxygen atom (n­(O)) and the antibonding σ*-orbital of the O–C bond (σ*­(O–C)) in 2OOBr, resulting in an orbital interaction energy (E ⁽²⁾) as small as −0.01 kcal mol^–1. In contrast, the overlap between n­(O) and σ*­(H–C) or σ*­(S–C) orbitals in 3SOBr and 2SOBr yields considerably more negative E ⁽²⁾ values (−0.41/–0.13 kcal·mol^–1 for H···O and −0.88/–1.31 kcal·mol^–1 for S···O), consistent with stronger NoCLs for the latter compounds. Moreover, the quantum theory of atoms in molecules (QTAIM) is adopted to search for the bond critical points (BCPs) of the electron density by the Multiwfn program. In 2OOBr, there are no BCPs between the carbonyl oxygen atom and the oxygen atom of the furan ring. In contrast, clear BCPs between the H­(S) atom and the O atom are identified in 3SOBr and 2SOBr due to the existence of NoCLs (Figure b). The electron densities ρ(r) at BCP of O···O, H···O, and S···O NoCLs are 0.000, 0.013, and 0.022 for 2OOBr, 3SOBr, and 2SOBr, respectively. Overall, these results consistently demonstrate a progressive strengthening of the intramolecular conformational locks from O···O to H···O and further to S···O interactions.

To probe and establish the relationship between the introduction of intramolecular interactions and the resultant emission bandwidth, the triplet excited states (T₁) geometries were also optimized at the M06-2X­(D3)/6-31+G­(d) level, and the reorganization energies between the S₀ and T₁ states were calculated with MOMAP. − The total reorganization energy shows a pronounced decreasing trend in the order of 2OOBr (4005 cm^–1) > 3SOBr (3365 cm^–1) > 2SOBr (616 cm^–1). To uncover the origin of this trend, we analyze the contributions of the normal modes (ω _i) to the reorganization energies (λ _i) in Figure a–c. The results reveal that the introduction of relatively weak H···O interaction in 3SOBr effectively suppresses the stretching vibration in the high-frequency regime. Upon further incorporation of stronger S···O NoCL in 2SOBr, inter-ring scissoring and torsional vibrations in the low-frequency regime are additionally restrained. Specifically, in 2OOBr, multiple frequency vibrational modes contribute with large reorganization energies at 12, 24, 1836, and 1818 cm^–1. In 3SOBr, the contributions from high-frequency modes are noticeably suppressed. In particular, the CO stretching vibration at 1825 cm^–1 exhibits a fivefold reduction, indicating effective attenuation of the electron-vibrational coupling. And in 2SOBr, the normal modes become blunt, and only a single high-frequency mode at 1812 cm^–1 remains significant. These results demonstrate that introducing noncovalent interactions with increasing S enables selective and stepwise suppression of structural relaxation pathways, thereby substantially reducing λ (Figure c). Further insights are obtained from the simulated phosphorescence spectra shown in Figure d–f. The phosphorescence spectra were calculated using the thermal vibration correlation function method and the sum-over-states method, respectively, enabling the obtaining of the contribution of the individual vibronic peaks to the whole spectra. The high-frequency modes (51 and 52) dominate the spectral broadening in 2OOBr. Increasing S suppresses vibronic broadening, reducing the FWHM from 107 to 78 nm and then to 23 nm for 2OOBr, 3SOBr, and 2SOBr, respectively. The excellent agreement between the simulated spectra and the vibrational analyses confirms that the targeted suppression of vibrational contributions effectively reduces vibronic sidebands, thereby leading to a narrowed emission spectrum. Therefore, as shown in Figure d, there is a good reverse correlation between descriptor S and FWHM, and S can be used to design ORTP materials with narrowband spectra.

3.

Reorganization energy of each normal mode versus mode frequency ω _i of (a) 2OOBr, (b) 3SOBr, and (c) 2SOBr. The calculated triplet emission spectra and the assignments of typical peaks with n ^m , where n is the normal mode index and m the vibrational quantum number of (d) 2OOBr, (e) 3SOBr, and (f) 2SOBr.

Having established how NoCLs regulate the emission bandwidth via vibrational suppression, we next turn to the excited-state electronic properties that govern the luminescence efficiency. Upon photoexcitation, the system relaxes along an S_n → S₁ → T_n → T₁ → S₀ pathway, giving rise to phosphorescence emission. Therefore, the ISC processes from S₁ to T_n (n = 1–3) are critical in determining the phosphorescence efficiency, as illustrated in Figure a–c. Within the Marcus framework, the ISC rate is governed by both ξ and the singlet-triplet energy gap (ΔE). Notably, for three molecules, the S₁–T₃ channel exhibits large ξ values, reaching up to ∼10² cm^–1. This strong ξ firstly originates from the favorable orbital character transition between S₁ (n→π*) and T₃ (π→π*) with substantial spatial overlap, which is allowed by El-Sayed’s rule. As seen in Figure d, γ increases from 2OOBr to 3SOBr and 2SOBr, resulting in the corresponding increase in ξ. On the other hand, the heavy-atom effect is introduced by multiple Br atoms with large proportions (25%–37%) in the frontier molecular orbitals (Table S4). Moreover, as shown in Figure e, with increasing conformational rigidity quantified by the S from 2OOBr to 3SOBr and 2SOBr, the molecular orbitals become more delocalized, leading to a progressive reduction in the S₁–T₃ energy gap. As a result, the combination of reduced ΔE and increased ξ in the S₁–T₃ channel effectively accelerates the ISC processes. This trend is consistent with the experimentally observed phosphorescence quantum yields (Φ _P) of 4.83%, 5.95%, and 58.22% for 2OOBr, 3SOBr, and 2SOBr, respectively.

4.

Calculated energy gaps (eV) and natural transition orbitals (NTOs) between singlet and triplet states based on the optimized T₁ geometry for (a) 2OOBr, (b) 3SOBr, and (c) 2SOBr. (d) Spin–orbit coupling (ξ) and γ. (e) Energy gap (ΔE _S1–T3) between S₁ and T₃ and S of the T₁ geometry structure of 2OOBr, 3SOBr, and 2SOBr.

Based on the above theoretical analysis, three compounds (2OOBr, 3SOBr, and 2SOBr) with different intramolecular interactions were synthesized (Figure a). Detailed synthetic procedures and characterization data are provided in Supporting Notes S1. Their chemical structures were confirmed by ¹H and ¹³C NMR in Supporting Notes S2. Single crystals of 2OOBr, 3SOBr, and 2SOBr were obtained by slow evaporation from chloroform (CHCl₃)/hexane solutions for X-ray diffraction (Table S5). Consistent with the introduction and strengthening of NoCLs, the dihedral angle between the benzophenone core and the adjacent aromatic unit decreases from 60.37° in 2OOBr to 57.08° in 3SOBr and 2.15° in 2SOBr (Figure a), indicating a pronounced increase in molecular planarity, in good agreement with the trend in the conformational lock strength descriptor S. The photophysical properties of the three compounds were subsequently investigated and are summarized in Table . In dilute 2-methyltetrahydrofuran solution, 2OOBr and 3SOBr exhibited only fluorescence, whereas 2SOBr showed an additional phosphorescence band under ambient conditions (Figure S1), indicative of a more efficient ISC process even in the presence of oxygen. Encouragingly, the experimentally measured FWHM of the phosphorescence spectrum is 29 nm in dilute solution, which is in good agreement with the calculated value of 23 nm for isolated 2SOBr. When doped into the PMMA matrix (5 wt %), oxygen diffusion was effectively suppressed, and all three films displayed phosphorescence-dominated emission (Figure b). Notably, the emission bandwidth and Φ _P showed a clear dependence on NoCL strength. The FWHM was reduced from 58 nm for 2OOBr and 50 nm for 3SOBr to 36 nm for 2SOBr, while Φ _P increased from 4.83% and 5.95% to 58.22% (Figure c), respectively. The phosphorescence bandwidth of 2SOBr naturally broadens from 29nm in dilute solution to 36 nm in PMMA owing to inhomogeneous, conformational variations and other solid-state environmental effects. These trends are fully consistent with the theoretical predictions based on reduced EVC and enhanced γ.

5.

(A) Single-crystal structures of 2OOBr, 3SOBr, and 2SOBr in top view (up) and side view (down). The key distances between atoms and dihedral angles are marked. (b) Steady-state PL spectra of three compounds doped in PMMA films in an ambient atmosphere. (c) The correlation between experimental FWHM and Φ _p and calculated S and γ. (d) The normalized cross-sectional intensity profiles. (e) Fluorescence images of HeLa cells co-stained with FluoLysoTM Deep Red and 2SOBr NPs (30 μg mL^–1). Scale bar = 30 μm (f) The biodistribution of 2SOBr NPs after injection in the jaw of nude mice at different time points.

1. Photophysical Properties of Three Compounds in 5 w.t%-Doped PMMA.

compound	λ abs (nm)	λem (nm)	FWHM (nm)	τF (ns)	ΦF (%)	τP (μs)	ΦP (%)
2OOBr	264, 300	536	58	0.53	0.40	73.91	4.83
3SOBr	319	554	50	0.60	0.28	29.51	5.95
2SOBr	323	558	36	0.70	0.34	85.13	58.22

^aThe UV–vis absorption peaks.

^bEmission peaks.

^cFull width at half maxima.

^dFluorescence lifetime.

^eFluorescence quantum yields.

^fPhosphorescence lifetime.

^gPhosphorescence quantum yields in the film state at room temperature.

To further assess the roles of the descriptors and the heavy-atom effect, the corresponding Cl-substituted (2OOCl, 3SOCl, and 2SOCl) and bromine-free analogues (2OO, 3SO, and 2SO) were investigated (Table S6). Replacing Cl with Br enhances the ξ and confirms the contribution of the heavy-atom effect. Meanwhile, within the Br/Cl-containing series, the progressive increase in γ from 2OOBr­(Cl) to 2SOBr­(Cl) is accompanied by increasing ξ, highlighting the role of orbital compatibility in promoting singlet-triplet coupling. For the bromine-free analogues, S and γ show an increase from 3SO to 2OO and 2SO, consistent with the corresponding variations in the experimentally measured phosphorescence FWHM and Φ _P (Figure S2). These results further support the descriptor-based relationship between molecular structure, vibronic broadening, and ISC efficiency across the investigated molecular series.

Given its narrowest emission bandwidth and highest Φ _P, 2SOBr was further formulated into nanoparticles (NPs) for biomedical imaging studies. The resulting 2SOBr NPs exhibited hydrodynamic diameters of 80–160 nm with a low polydispersity index (0.08), as determined by dynamic light scattering (DLS), consistent with transmission electron microscopy (TEM) observations (Figure S3). To evaluate whether the RTP characteristics are preserved in aqueous environments, the emission of 2SOBr NPs was investigated in water. The NPs retained photophysical properties comparable to those in the PMMA matrix, displaying a phosphorescence FWHM of 38 nm, a Φ _P of 29.39%, and a lifetime of 117.6 μs (Figure S4). The reduced Φ _P of NPs is attributed to serious oxygen quenching, as confirmed by the increase from 29.39% in water to 36.97% under nitrogen, and slightly enhanced vibronic relaxation in the softer nanoparticle environment, while the retained FWHM of 38 nm confirms the persistent conformational restriction by NoCLs. This preservation of narrowband and efficient emission indicates that the molecular design effectively maintains suppressed EVC and efficient ISC in dispersed states.

On this basis, the biocompatibility and cellular imaging performance were further examined. Cytotoxicity evaluation using a Cell Counting Kit-8 (CCK-8) assay with HeLa cells shows no significant decrease in cell viability up to 200 μg mL^–1 (Figure S5) and 72 h (Figure S6–S7), indicating good biocompatibility. After co-incubation with HeLa cells for 12 h, the NPs were efficiently internalized, as evidenced by strong intracellular luminescence. After irradiation, 2SOBr NPs showed negligible intracellular RTP decay and almost unchanged UV–vis absorption spectra, supporting their good photostability and chemical stability. Benefiting from narrowband phosphorescence and reduced background interference, cellular imaging achieved a high SNR of 15.93 (Figure d), highlighting the effectiveness of spectral confinement in suppressing biological autofluorescence. To further identify the intracellular distribution, co-localization experiments using FluoLyso Deep Red as a lysosomal marker revealed a high Pearson correlation coefficient of 98.01% (Figures e and S8), confirming preferential accumulation of 2SOBr NPs in lysosomes. The in vivo imaging performance of 2SOBr NPs was finally evaluated in nude mice. No acute toxicological responses were observed during the experiments. Following subcutaneous injection of 2SOBr NPs (17.97 mg kg^–1), fluorescence signals were clearly detected over time in the neck region (Figures f and S9). The high SNR demonstrated that 2SOBr NPs retain sufficient contrast for imaging in complex biological environments.

Conclusion

In conclusion, we have established and experimentally validated a descriptor-guided framework for achieving efficient and narrowband ORTP tailored for high-contrast bioimaging. Guided by theoretical analysis, the NoCL strength descriptor S and the orbital character descriptor γ were employed to predict FWHM and Φ _P. These descriptor-based predictions were subsequently confirmed experimentally, establishing a clear correspondence between calculated descriptor values and measured photophysical performance. Consistent with its highest S (0.75) and γ (2.32%) values, 2SOBr exhibits narrowband ORTP with an FWHM of 36 nm and a Φ _P of 58.22% under ambient conditions. Importantly, the same descriptor-guided correlations are further validated in an additional molecular system, demonstrating the generality and predictive power of our framework. In biological applications, 2SOBr NPs enable lysosome-specific cellular imaging with a high SNR of 15.93 and further support in vivo imaging. Overall, these results demonstrate that descriptor-guided conformational control provides a predictive and experimentally validated route to RTP probes that combine high efficiency, spectral purity, and practical bioimaging performance.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.6c01042.

• Experimental details (synthetic procedures, reaction reagents, structural characterization data, X-ray data, and photophysical properties characterization), supplementary tables and figures, descriptor analysis, and biological measurements (PDF)

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M.L., X.Q., and Z.L. contributed equally to this work.

The authors declare no competing financial interest.