Recent advances in the chemical design and synthesis of fluorophores in the second near-infrared biological window (NIR-II) for multimodal imaging and theranostics are summarized and highlighted in this review article.

Intrinsically stretchable bioelectronic devices based on soft and conducting organic materials have been regarded as the ideal interface for seamless and biocompatible integration with the human body. A remaining challenge is to combine high mechanical robustness with good electrical conduction, especially when patterned at small feature sizes. We develop a molecular engineering strategy based on a topological supramolecular network, which allows for the decoupling of competing effects from multiple molecular building blocks to meet complex requirements. We obtained simultaneously high conductivity and crack-onset strain in a physiological environment, with direct photopatternability down to the cellular scale. We further collected stable electromyography signals on soft and malleable octopus and performed localized neuromodulation down to single-nucleus precision for controlling organ-specific activities through the delicate brainstem.

Fluorescence imaging in the second near-infrared window (NIR-II) allows visualization of deep anatomical features with an unprecedented degree of clarity. NIR-II fluorophores draw from a broad spectrum of materials spanning semiconducting nanomaterials to organic molecular dyes, yet unfortunately all water-soluble organic molecules with >1,000 nm emission suffer from low quantum yields that have limited temporal resolution and penetration depth. Here, we report tailoring the supramolecular assemblies of protein complexes with a sulfonated NIR-II organic dye (CH-4T) to produce a brilliant 110-fold increase in fluorescence, resulting in the highest quantum yield molecular fluorophore thus far. The bright molecular complex allowed for the fastest video-rate imaging in the second NIR window with ∼50-fold reduced exposure times at a fast 50 frames-per-second (FPS) capable of resolving mouse cardiac cycles. In addition, we demonstrate that the NIR-II molecular complexes are superior to clinically approved ICG for lymph node imaging deep within the mouse body.

Developing multifunctional and easily prepared nanoplatforms with integrated different modalities is highly challenging for molecular imaging. Here, we report the successful transfer of an important molecular target, melanin, into a novel multimodality imaging nanoplatform. Melanin is abundantly expressed in melanotic melanomas and thus has been actively studied as a target for melanoma imaging. In our work, the multifunctional biopolymer nanoplatform based on ultrasmall (<10 nm) water-soluble melanin nanoparticle (MNP) was developed and showed unique photoacoustic property and natural binding ability with metal ions (for example, ⁶⁴Cu²⁺, Fe³⁺). Therefore, MNP can serve not only as a photoacoustic contrast agent, but also as a nanoplatform for positron emission tomography (PET) and magnetic resonance imaging (MRI). Traditional passive nanoplatforms require complicated and time-consuming processes for prebuilding reporting moieties or chemical modifications using active groups to integrate different contrast properties into one entity. In comparison, utilizing functional biomarker melanin can greatly simplify the building process. We further conjugated α_vβ₃ integrins, cyclic c(RGDfC) peptide, to MNPs to allow for U87MG tumor accumulation due to its targeting property combined with the enhanced permeability and retention (EPR) effect. The multimodal properties of MNPs demonstrate the high potential of endogenous materials with multifunctions as nanoplatforms for molecular theranostics and clinical translation.

Optical imaging of diseases represents a highly dynamic and multidisciplinary research area, and second near-infrared window (NIR-II, 1000–1700 nm) imaging is at the forefront of the research on optical imaging techniques. Small-molecule based NIR-II (1000–1700 nm) dyes are highly promising candidates for in vivo molecular imaging because of their high biocompatibility, fast excretion, and high clinical translation ability. However, research reports on small-molecule based NIR-II dyes and probes are rare. Herein, we designed a series of fluorescent compounds (Q1, Q2, Q3, and Q4) and investigated the relationships between their structures and absorption/fluorescence properties. Q4 (maximum emission at 1100 nm) stood out as the dye with the best physical properties and thus was selected as a scaffold for the facile construction of two types of water-soluble and biocompatible NIR-II probes (Q4NPs and SCH1100). Highly specific gastrin-releasing peptide receptor (GRPR) targeted NIR-II imaging of prostate cancer in living mice was achieved using the small-molecule probe SCH1100, which represents the first small peptide based NIR-II probe for targeted cancer imaging. The attractive imaging properties of Q4-based NIR-II probes open up many opportunities for molecular imaging and clinical translation in the unique NIR-II window.