520
3 Exosomes
Exosomes are nanoscale extracellular vesicles( EVs), typically 30 – 150 nm in diameter, released by most cell types through the endosomal pathway. They carry a rich molecular cargo of proteins, lipids, metabolites, and nucleic acids( DNA, mRNA, miRNA), which closely reflects the physiological and pathological state of their parental cells [ 18, 19 ]. Because exosomes are abundant and stable in virtually all biofluids( blood, urine, saliva, cerebrospinal fluid), they can be collected in a minimally invasive manner by liquid biopsy and are therefore highly attractive as early-stage cancer biomarkers [ 20, 21 ]. Tumour-derived exosomes exhibit characteristic alterations in their cargo composition – in particular in protein and nucleic-acid content – and encode cancer-type-specific signatures that can be exploited for diagnosis, patient stratification, and therapy monitoring [ 17, 23, 24 ].
From an optical-sensing perspective, these biochemical alterations manifest as subtle changes in the exosome’ s effective refractive index( ERI), which can in principle be detected by sufficiently sensitive label-free photonic biosensors [ 16, 42 ]. The present work builds on this concept by linking the protein and nucleic-acid( NA) content of single exosomes to their ERI and, in a second step, to the resonance response of high-Q f WGM microresonators.
3.1 Core – shell geometric model of the exosome
A single exosome is modeled as a concentric core – shell sphere embedded in an aqueous host medium and numerically analyzed in Comsol Multiphysics. The core represents the lumen, an aqueous solution of proteins and nucleic acids( NA), while the shell represents the lipid bilayer membrane. Consistent with electron microscopy and membrane biophysics, the outer radius of the exosome is taken as a = 45.5 nm, and the lipid bilayer shell thickness as t shell = 5 nm, so that the lumen radius is b = a � t shell = 40.5 nm [ 43 ]. The lipid shell is modeled as a non-absorbing layer with slightly dispersive refractive index around n shell’ 1.48 in the visible / near-IR, in line with spectroscopic studies of supported lipid bilayers and vesicles [ 44 – 47 ]. The host medium is taken as water with dispersive refractive index n water( k)[ 48 ].
Within this framework, the only degrees of freedom that encode the biological state of the exosome are the lumen composition( protein and NA concentrations) and, to a lesser extent, the detailed lipid composition of the membrane. In this study we focus on the lumen composition as the primary contrast mechanism between healthy-like and cancerderived exosomes.
3.2 Lumen refractive index from the Barer relation
The refractive index of the exosome lumen is computed in MATLAB using the classical two-substance( Barer) relation for aqueous macromolecular solutions [ 49 ]. For an aqueous mixture of proteins and nucleic acids at mass concentrations c prot and c NA( in g mL �1), the lumen refractive index can be written as
J. Eur. Opt. Society-Rapid Publ. 22, 53( 2026)
n core ðÞ¼n k water ðÞþ k
dn dc c prot þ prot
dn dc c NA;
NA ncore H core k ð3Þ
where( dn / dc) prot and( dn / dc) NA are the refractiveindex increments( RII) of proteins and nucleic acids, respectively. In the visible range at ambient temperature, robust consensus values are( dn / dc) prot 0.190 mL g �1 and( dn / dc) NA 0.170 mL g �1, with only weak dispersion [ 50, 51 ].
Guided by experimental reports that place the effective refractive index of extracellular vesicles in the range n eff 1.37 – 1.40 in the visible [ 16, 26, 42 ], we select biologically plausible concentration bands for healthy-like and cancer-like exosomes. Healthy-like exosomes are assigned protein and NA concentrations in the lower part of the band, while cancer-derived exosomes are assigned elevated concentrations, consistent with the increased protein and NA cargo typically observed in tumour-derived EVs [ 21, 52 ]. Evaluating equation( 3) for these concentration bands yields three representative lumen refractive indices: ð Þ ð k
C
Þ for healthy exosomes, n ð Þ ð Þ for cancerous exosomes, and intermediate values n ð core BÞ ð k Þ for“ borderline” exosomes whose protein / NA content lies between the two regimes.
Figure 2 summarizes the resulting n core( k) forthese three classes in the wavelength range relevant to our microresonator WGMs.
3.3 Effective refractive index of the whole exosome
To obtain an effective refractive index for the entire exosome( core plus lipid shell), a full-wave driven-mode simulation of the core – shell sphere in Comsol Multiphysics is carried out. The reason for considering exosomes as core – shell structures is to increase the sensitivity to the slightest changes in the core, i. e. variations in the protein / NA content. Consistent with this modeling objective, variations in the lipid bilayer are not explicitly included, and the membrane is treated as having fixed thickness and refractive index. While biologically relevant variations in membrane composition may also contribute to the overall effective refractive index of the exosome, this effect is beyond the scope of the present study and will be addressed in future sensitivity analyses. Within this framework, the model can be regarded as conservative, as it isolates the lumen contribution and enables a clear characterization of lumen-composition-induced contrast.
The core – shell exosome model described above is illuminated by a plane wave in the 500 – 900 nm spectral range, and the electric field E( r) and the electric flux density D( r) inside the whole exosome volume V p( core plus shell) are computed. The effective relative permittivity of the exosome is then retrieved via
e eff ¼ hDr ð Þi e 0 hEr ð Þi; ð4Þ
where ɛ 0 is the vacuum permittivity and hi denotes a volume average over V p. The effective refractive index of the exosome is then obtained as