Peptide Molecules "Breaking Symmetry" Enable Ultralow-Voltage Ferroelectric Materials and Promote Neuronal Growth

Today, we share groundbreaking research by the team of Samuel I. Stupp, published in Advanced Materials. This study successfully developed a water-soluble, self-assembling novel organic ferroelectric material by inducing symmetry breaking through peptide molecules. This material not only exhibits an ultralow driving voltage (±2.5 kV/cm) but also significantly promotes the growth of neuronal axons. This work opens a new avenue for developing water-processable, biocompatible ferroelectric biomaterials, bringing new possibilities for bioelectronic devices and neural regenerative medicine.

01 Research Background

Ferroelectric materials, due to their spontaneous polarization that can be reversed by an external electric field, hold significant application value in memory devices, electro-optic devices, and wearable electronics. Compared to inorganic ferroelectric materials, organic ferroelectrics offer advantages such as lightweight, low toxicity, and easy processing, showing great promise especially in biomedical applications like biosensing and tissue engineering. However, the number of reported organic ferroelectrics is limited, and their design strategies are far less mature than inorganic systems. In recent years, donor-acceptor charge-transfer cocrystals have been shown to generate second harmonic generation (SHG) and ferroelectricity by breaking centrosymmetry, but such materials are often difficult to process in aqueous phases, limiting their biological applications. Bioinspired supramolecular chemistry offers the potential to construct water-processable, biocompatible functional nanostructures. Studies indicate that coupling chromophores with peptide sequences can induce chirality, thereby enabling the development of symmetry-breaking properties in charge-transfer systems. This study aims to explore a peptide-induced symmetry-breaking strategy for designing novel supramolecular ferroelectric materials and validate their biological function in regulating neural cell behavior.

02 Innovative Highlights

• Covalent Integration of Donor-Acceptor with Peptides:

The research team designed and synthesized a novel class of molecules (DA-PAs), covalently linking an electron donor (alkoxy-substituted naphthalene) and an acceptor (pyromellitic diimide or naphthalene diimide) via a linker to an oligopeptide (single, di-, or tetrapeptide). This design pre-organizes the donor-acceptor pair intramolecularly and guides supramolecular self-assembly via the peptide, forming long-range ordered nanostructures, laying the foundation for ferroelectricity.

• Peptide Chirality Induces Non-centrosymmetric Lattice:

A key breakthrough in this study is the successful induction of symmetry breaking in the entire donor-acceptor assembly by utilizing the inherent chirality of the peptide units. Circular dichroism (CD) spectroscopy showed that DA-PAs containing chiral amino acids (e.g., lysine K, valine V) like DA1-K and DA1-VK produced strong signals in the absorption region of the chromophores, indicating the chromophores are in a chiral environment. Second harmonic generation (SHG) testing further confirmed that these assemblies possess a non-centrosymmetric crystalline structure, which is a prerequisite for ferroelectricity.

•  Achievement of Room-Temperature Ferroelectric and Piezoelectric Response:

The research team successfully measured clear polarization-electric field (P-E) hysteresis loops in dried DA-PA samples, confirming their ferroelectricity. For instance, DA2-VK exhibited a high remanent polarization (Pr) and a coercive field (Ec) of about ±2.5 kV/cm. Furthermore, under ultrasonic stimulation, ferroelectric DA-PA samples (e.g., DA2-VK) generated piezoelectric voltage signals matching the stimulation frequency, whereas non-ferroelectric samples (e.g., DA1) showed weak responses, demonstrating their electromechanical conversion capability.

• Ferroelectric Materials Promote Neuronal Growth and Maturation:

Culturing primary mouse cortical neurons on ferroelectric DA-PA coatings (e.g., DA1-VK, DA3-VK) found that these materials not only supported neuronal survival but also significantly enhanced the growth complexity of the axonal network and the amplitude of action potentials. This suggests that the inherent ferroelectric polarization of the material might enrich neurotrophic factors or ions via electrostatic interactions, mimicking the microenvironment that guides neuronal growth in vivo, thereby promoting neuronal functional maturation without requiring exogenous electrical stimulation.

03 Results and Discussion

3.1 Molecular Synthesis, Self-Assembly, and Charge Transfer Characterization

The study synthesized four donor-acceptor dyads (DA1-DA4) and their corresponding peptide conjugates (DA-PAs). X-ray single-crystal diffraction resolved the molecular structures of DA1, DA2, and DA3, showing they adopt an antiparallel packing, forming alternating donor-acceptor π-stacks. UV-Vis absorption spectroscopy indicated that DA1 in aqueous solution exhibited a broad absorption band at 400-550 nm, which disappeared in DMF, proving the existence of intermolecular charge-transfer interactions in aqueous solution as a result of supramolecular assembly. This charge-transfer band persisted after introducing peptide sequences (e.g., K, VK), indicating the assembly was maintained.

Figure 1. Molecular structures and self-assembly of the donor-acceptor peptide amphiphiles.

3.2 Nanostructure and Internal Crystallographic Characterization

Transmission electron microscopy (TEM) revealed that peptide-free DA1 self-assembled into ribbon-like structures over 5 micrometers long and about 200 nanometers wide. Selected area electron diffraction (SAED) confirmed its crystalline structure, with measured molecular spacings (a=7 Å, b=16 Å) consistent with single-crystal data. Introducing a single peptide (DA1-K) or a dipeptide (DA1-VK) resulted in polydisperse nanostructure morphologies but still maintained some ribbon-like features. SAED analysis revealed that the crystallographic parameters of DA1-VK changed, producing a new 2D rectangular lattice (a=7 Å, b=8 Å), indicating that the peptide introduction altered the molecular packing. Wide-angle X-ray scattering (WAXS) results corroborated the SAED findings.

Figure 2. Structural characterization of donor-acceptor peptide amphiphiles.

3.3 Experimental Verification of Symmetry Breaking and Ferroelectricity

CD spectroscopy confirmed that peptide introduction transferred chirality to the chromophore assembly. SHG imaging clearly showed that samples like DA1-K and DA1-VK possessed strong second harmonic signals, confirming the non-centrosymmetric nature of the overall structure, which is the basis for ferroelectricity. Key ferroelectric tests showed that DA2-VK possessed the most excellent ferroelectric properties. Its long ribbon-like nanostructures (about 3 μm) could bridge the gap between electrodes, allowing for the measurement of distinct P-E hysteresis loops. In contrast, DA1-VK with shorter nanostructures (<1 μm) or DA3-VK with weaker donor-acceptor interactions exhibited relatively weaker ferroelectric performance.

3.4 Biological Function Validation: Promoting Neuronal Growth and Electrophysiological Maturation

In vitrocell experiments showed that neuronal survival rates on coatings of ferroelectric materials DA1-VK and DA3-VK were comparable to, or even better than, the commonly used coating poly-D-lysine (PDL). Immunofluorescence staining and morphometric analysis revealed that neurons cultured on DA1-VK and DA3-VK had significantly larger network coverage areas for axons (SMI312 positive) and the overall neuronal cytoskeleton (Tuj1 positive) compared to the PDL control group and the non-ferroelectric DA1-K group. Whole-cell patch-clamp recordings further found that neurons cultured on ferroelectric DA1-VK had significantly higher action potential amplitudes than those on non-ferroelectric DA1-K, indicating more mature electrophysiological properties. The researchers speculate that the built-in electric field generated by the ferroelectric material might orderly distribute bioactive factors in the culture medium via electrostatic interactions, thereby guiding and promoting neuronal growth and maturation.

Figure 3. Primary cortical neuron survival and growth supported on coatings of donor–acceptor peptide amphiphile nanostructures.

04 Conclusion and Future Perspectives

This study successfully demonstrates a generalizable strategy for designing supramolecular ferroelectric materials through peptide-induced symmetry breaking. The core of this strategy lies in the covalent coupling of chiral peptides with donor-acceptor chromophores, utilizing the supramolecular self-assembly of peptides to guide the chromophores into forming non-centrosymmetric crystalline nanostructures, thereby generating ferroelectricity. The obtained DA-PA materials not only possess excellent ferroelectric and piezoelectric properties but can also effectively promote neuronal adhesion, axonal growth, and electrophysiological maturation in vitro, showing immense potential for biomedical applications.

The significance of this work lies in its precise alignment of the "bottom-up" assembly concept of supramolecular chemistry with the performance requirements of functional materials (ferroelectrics). Here, peptides serve not only as structure-directing units but also as key functional elements for achieving symmetry breaking. In the future, this strategy can be further extended in the following directions: ① By screening peptide sequences with different self-assembly propensities or modulating assembly conditions, precise control over nanostructure morphology and polarization could be achieved, thereby tailoring ferroelectric properties. ② Exploring the application of such materials in broader biomedical fields like nerve repair and bone tissue engineering. ③ Combining with advanced fabrication processes like continuous flow synthesis to promote the scaling and device integration of such soft-matter ferroelectric materials, providing a new material platform for next-generation bioelectronic interfaces and implantable medical devices.

Original Article：

Passarelli JV, Yang Y, Smith CS, Hao J, Dave DR, Narayanan A, Álvarez Z, Johnson BK, Marshall KA, Fithian I, Sai H, Qiu R, Stern CL, Palmer LC, Kiskinis E, Stupp SI. Peptide-Induced Ferroelectricity in Charge-Transfer Supramolecular Materials. Adv Mater. 2026 Jan 10:e14940. 

https://advanced.onlinelibrary.wiley.com/doi/10.1002/adma.202514940