NIR‐II absorbing organic nanoagents for photoacoustic imaging and photothermal therapy

Abstract

Near‐infrared (NIR) absorbing materials hold great potential in biomedical applications, such as fluorescence imaging (FLI), photoacoustic imaging (PAI), photodynamic therapy (PDT), and photothermal therapy (PTT). Generally, these materials can be classified into two main categories based on their absorbing wavelengths: the first NIR (NIR‐I) (~650–950 nm) absorbing materials and the second NIR (NIR‐II) (~1000–1700 nm) absorbing materials. Due to the reduced absorption and scattering of NIR‐II light in tissue compared to NIR‐I light, NIR‐II absorbing materials enable imaging and therapy with improved contrast and deepened penetration, which is in favor of practical applications. Various inorganic materials have been developed for NIR‐II phototheranostics in recent years. However, the non‐biodegradability and potential toxicity of these materials hinder their further clinical translation. Biocompatible organic materials with potential biodegradability as well as tailored optical property are thus more desired. In this review, we summarize the recent advances of NIR‐II absorbing organic nanoagents (ONAs) based on small molecules (SMs) and conjugated polymers (CPs) for PAI and PTT and show our perspectives on future challenges and development of these materials.

INTRODUCTION

With the aid of near-infrared (NIR) light excitation, phototheranostics can simultaneously perform diagnosis and therapy for diseases through various imaging and therapeutic modalities. Among them, photoacoustic imaging (PAI) and photothermal therapy (PTT) emerged as promising phototheranostics in recent years due to the rapid development of NIR absorbing materials. The working principle of these materials is that when they are excited by NIR light, they undergo electron transfer to form the excited state, which is then relaxed to the ground state through non-radiative relaxation with heat release to perform PTT for disease treatment (tumor, antibacterial, etc.). For PAI, it utilizes the photothermal effect of PTT agents to produce an acoustic signal for biomedical imaging (tumor, vascular, cerebral, etc.). PAI has some inherent advantages over conventional fluorescence imaging (FLI) such as deep penetration, high contrast, and excellent stability. NIR absorbing material-enabled phototheranostics (PAI/PTT) are noninvasive and highly efficient with low side effects compared to conventional surgery, chemotherapy, and radiotherapy. More practically, PAI/PTT can cooperate with other imaging and therapeutic modalities to achieve multimodal theranostics for improved outcomes.

Based on their absorbing wavelengths, NIR phototheranostic materials can generally be classified into two main categories: the first NIR (NIR-I) (~650–950 nm) absorbing materials and the second NIR (NIR-II) (~1000–1700 nm) absorbing materials. The wavelength of the laser employed in phototheranostics is crucial for imaging and therapeutic outcome due to the different interactions of lasers with the tissue under different wavelengths. NIR-II light shows two advantages over NIR-I light. First, it possesses deeper tissue penetration and weaker auto-fluorescence compared to NIR-I light as a result of its reduced absorption and scattering in tissues (Figure ). Second, the maximum permissible exposure (MPE) of NIR-II light is much higher than that of NIR-I light. According to ANSI Z136.1-2007 (American National Standard for Safe Use of Lasers), MPE for skin exposure is 1 W cm⁻² at 1000–1100 nm, compared to 0.33 W cm⁻² at 808 nm. Given the water absorption in tissue at ~1450 nm, NIR-II window can be further split into two subwindows: NIR-IIa (1300–1400 nm) and NIR-IIb (1500–1700 nm). NIR-II light with wavelengths in these two ranges will avoid water absorption. As such, NIR-II phototheranostics can achieve imaging with improved contrast and amplified therapeutic effect, which may eventually promote their clinical translation for practical applications.

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Various inorganic materials have been developed for NIR-II phototheranostics in recent years. Despite the satisfactory performance of these materials, the non-biodegradability and potential toxicity originating from their inorganic nature restrict their further applications. Emerging organic materials with considerable biodegradability and easily tunable optical properties are thus more desired in NIR-II phototheranostics. In this review, we comprehensively summarize the recent advances of NIR-II absorbing phototheranostic organic nanoagents (ONAs) prepared from both small molecules (SMs) and conjugated polymers (CPs) through the nanoprecipitation method assisted by amphiphilic polymer matrixes, differentiating from previous reviews that only report SMs or CPs. We also show our perspectives on future challenges and development of these materials at the end of this review.

SM-BASED ONAS

SMs with well-defined chemical structure, excellent optical property, and high photochemical stability play a critical role in diverse applications, including bioimaging, chemosensors, and organic electronics. Although quite a lot of SMs have been synthesized and utilized in phototheranostics, most of them are NIR-I active. To date, reports of SMs for NIR-II phototheranostics are still rare.

In this section, we aim to give some examples of recently developed SMs for NIR-II phototheranostics in terms of PAI and PTT. These examples mainly include small molecular dye derivatives, nickel (II) dithiolene complexes, and donor–acceptor (D–A) conjugated SMs (Figure , Table ).

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TABLE 1 Summary of the properties and applications of the SM-based ONAs

ONAs	Operating wavelength (nm)	PTCE (%)	Application	Ref.
SM1 (croconaine)	980	N.A.	Glioma imaging
SM2 (phthalocyanine)	1064	58.3	NIR-II PTT of MCF-7 tumor
SM3 (phthalocyanine)	1064	64.7	NIR-II PTT of MCF-7 tumor
SM4 (Ni2+ dithiolene complex)	1064	N.A.	NIR-II PAI of sentinel lymph nodes
SM5 (Ni2+ dithiolene complex)	1064	63.6	NIR-II PTT of HeLa cells
SM6 (D–A conjugated SM)	808/1064	28.8/31.6	PAI-guided NIR-II PTT of HuH-7 tumor
SM7 (D–A conjugated SM)	1064	77	PAI-guided NIR-II PTT of 4T1 tumor
SM8 (D–A conjugated SM)	1064	80	PAI-guided NIR-II PTT of 4T1 tumor
SM9 (D–A conjugated SM)	1064	49	NIR-II photothermal antibacterial therapy

Small molecular dye derivatives

Conventional small molecular dyes generally exhibit remarkable light absorption and high fluorescence quantum yield thus enabling their efficient phototheranostics. Current phototheranostic small molecular dyes are porphyrin, phthalocyanine (Pc), borondipyrromethane (BODIPY), cyanine, and squaraine derivatives. Despite the satisfactory phototheranostic performance of these SMs, their absorbing wavelengths lie in the less favorable NIR-I region with limited tissue penetration. NIR-II absorbing small molecular dyes are in urgent demand, however, the development of such SMs is still in its infancy.

Liu and coworkers developed a croconaine dye SM1 and prepared J-aggregated SM1-based ONAs with a DSPE-PEG2000 polymer matrix. SM1-based ONAs are spherical nanoparticles with a size of around 130 nm as revealed by transmission electron microscopy (TEM) (Figure ). PAI of mouse brain glioma can be achieved at both 970 and 1200 nm due to strong absorption of SM1-based ONAs in the range of 850–1250 nm. Comparison of the signal-to-background ratio (SBR) of PAI at 970 and 1200 nm suggests the deeper tissue penetration of NIR-II light thus affording a higher SBR at 1200 nm (Figure ). Another NIR-II absorbing small molecular dye derivative SM2 featuring a cruciform phthalocyanine structure was synthesized by Pan et al. By using the same matrix of DSPE-PEG2000, SM2 was prepared to form spherical nanoparticles (SM2-based ONAs) with sizes of 40–70 nm (Figure ). Thanks to the NIR-II absorption of SM2-based ONAs, MCF-7 tumor mice were successfully cured by NIR-II PTT (Figure ). Later, a simple single-molecular phosphorus phthalocyanine SM3 was developed by Zhou et al. and the SM3-based ONAs were also used for NIR-II PTT of MCF-7 tumor.

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Nickel (II) dithiolene complexes

Metal dithiolene complexes are a kind of NIR absorbing materials and their absorbing wavelengths can be readily adjusted using the metal center and dithiolene substituent. Previous studies have focused on their electronic structure, absorption/emission property, redox property, and magnetic activity. Among these complexes, nickel (II) dithiolene complexes are quite popular due to their intensive NIR absorption, efficient photothermal conversion, and good photochemical stability.

To develop NIR-II absorbing nickel (II) dithiolene complexes, researchers have been devoted to modulating their absorption by regulating the peripheral ligands. For instance, Park et al. reported bis(4-dimethylaminodithiobenzil) nickel (II) (SM4)-based ONAs for NIR-II deep tissue PAI for the first time. These ONAs were prepared from SM4 and PLGA through a nanoprecipitation method and their size is about 130 nm (Figure ). Given the ligand effect of the 4-dimethylaminodithiobenzil group, SM4-based ONAs possess a strong absorption peak at 1064 nm, which is favorable for NIR-II deep tissue PAI with an improved signal-to-noise ratio (SNR) (Figure ). In addition, Chen et al. used bis(fluorenyl) dithiolene as the ligand to construct nickel (II) dithiolene complex SM5. They used amphiphilic Pluronic F127 to formulate SM5-based ONAs as spherical nanoparticles with a size of 67 nm (Figure ). However, only in vitro NIR-II PTT was conducted on a cellular level (HeLa cells) despite the high photothermal conversion efficiency (PTCE) of SM5-based ONAs (Figure ).

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D–A conjugated SMs

D–A conjugated SMs are constructed from electron-rich donors and electron-deficient acceptors. With efficient intramolecular charge transfer (ICT) caused by the strong D–A interaction inside the molecules, they are excellent light absorbers with high extinction coefficients. Additionally, the absorption of these SMs can be easily tuned by simply changing the D–A pairs. According to the linking style of the donor and acceptor segment, D–A conjugated SMs can be divided into different types, such as D–A, D–A-D, A–D–A, and so on. Numerous D–A conjugated SMs have been explored based on diverse donors and acceptors for emerging applications, especially organic electronics, such as organic solar cells (OSCs), organic light-emitting diodes (OLEDs), and organic field-effect transistors (OFETs).

For the biomedical application of D–A conjugated SMs, they are exploited as NIR-I phototheranostics. The reports of NIR-II phototheranostics based on D–A conjugated SMs have rarely been seen. In 2020, Shao et al. synthesized a D–π–A–π–D structured SM6 with triphenylamine (TPA) as the donor, benzo[1,2-c:4,5-c’]bis([1,2,5]thiadiazole) (BBT) as the acceptor, and two thiophene rings as the π-bridge. The extended conjugation contributes to NIR-II absorption of SM6. After encapsulation of SM6 into Pluronic F127 micelles, SM6-based ONAs were obtained as spherical nanoparticles, typically exhibiting high NIR-II photothermal conversion and effective PAI in vitro. In vivo PAI of HuH-7 tumor mice was subsequently performed with SM6-based ONAs (Figure ). Finally, under the guidance of PAI, NIR-II PTT inhibited tumor growth with high efficacy. More importantly, staining of tumor slices treated with NIR-I and NIR-II laser implies the deeper tumor penetration of NIR-II laser, which is beneficial for the NIR-II PTT of the deep-seated tumor with SM6-based ONAs (Figure ). Later, Li et al. further substituted the sulfur atoms in BBT unit to more heavy selenium atoms to afford a new acceptor, which was then linked with the donor of fluorene through a thiophene bridge to yield SM7. SM7-based ONAs display prominent NIR-II PAI and PTT efficacy against 4T1 tumors. Except for a BBT-like structure, some other acceptors have also been exploited. Jiang et al. used 1,2-bis(4-N,N-dioctylaminophenyl)-1,2-diphenylethene as a donor and borondifluoride-bridged azafulvene dimer as an acceptor to give SM8. SM8-based ONAs realized ultrahigh NIR-II PTCE of 80%. Such properties of SM8-based ONAs ensure their highly efficient NIR-II phototheranostics of 4T1 tumors in vivo (Figure ). Another kind of D–A conjugated SMs with an A–D–A structure are well-studied non-fullerene small molecular acceptors in bulk heterojunction OSCs. Jia et al. employed such a structured SM9 for SM9-based ONAs, which were then utilized in NIR-II photothermal antibacterial therapy of Staphylococcus aureus (S. aureus) for the first time.

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CP-BASED ONAS

Compared with SMs, CPs are polymers linked by the donor and acceptor in an alternative fashion with extended conjugation, therefore, their light absorption is generally elevated. Moreover, similar to D–A conjugated SMs, the absorption wavelength of CPs can readily be adjusted by rational D–A selection. Numbers of CPs derived from a variety of donors and acceptors are popular organic semiconductors for organic electronics especially the polymer OSCs with high performance. Considering their outstanding optical properties and inherent biocompatibility, CPs are emerging materials for phototheranostics.

In this section, we describe NIR-II phototheranostic CP-based ONAs in terms of the acceptor structure: isoindigo (IID), [1,2,5]thiadiazolo[3,4-g]quinoxaline (TQL), BBT, and thiadiazolobenzotriazole (TBZ) (Figure , Table ). Generally speaking, all of these acceptors can combine with appropriate donors for CPs with reasonable PAI/PTT performance. However, there are structural differences among them. For example, the side chains in IID, TQL, and TBZ will provide more opportunities for structural modification to afford more high performance CPs compared to BBT with no side chains.

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TABLE 2 Summary of the properties and applications of the CP-based ONAs

ONAs	Operating wavelength (nm)	PTCE (%)	Application	Ref.
CP1 (IID-based CP)	1064	49.5	NIR-II PTT of HeLa tumor
CP2 (IID-based CP)	1064	66.4	PAI-guided NIR-II PTT of MDA-MB-231 tumor
CP3 (IID-based CP)	1064	50	PAI-guided NIR-II PTT of HeLa tumor
CP4 (IID-based CP)	1064	45.8	NIR-II PTT of HeLa tumor
CP5 (IID-based CP)	1064	72.9	PAI-guided NIR-II PTT of 4T1 tumor
CP6 (TQL-based CP)	1064	21.2	PAI-guided NIR-II PTT of U87 tumor
CP7 (TQL-based CP)	860/1064	N.A.	Stem cells tracking
CP8 (TQL-based CP)	808/1064	61.6 (1060 nm)	Tumor growth monitoring
CP9 (TQL-based CP)	1064	34.9	NIR-II PTT of MDA-MB-231 tumor
CP10 (TQL-based CP)	750/1064	N.A.	Vascular imaging
CP11 (TQL-based CP)	808/1064	44.9/43.4	NIR-II PTT of 4T1 tumor
CP12 (BBT-based CP)	1064	N.A.	NIR-II PAI-guided rheumatoid arthritis therapy
CP13 (BBT-based CP)	1064	30.1	PAI-guided NIR-II PTT of U87 tumor
CP14 (BBT-based CP)	1064	53	Tumor and brain vascular imaging
CP15 (BBT-based CP)	1064	65	PAI-guided NIR-II PTT of HepG-2 tumor
CP16 (BBT-based CP)	808/1064	31.1/46.0	NIR-II PTT of orthotopic liver cancer
CP17 (TBZ-based CP)	1064	53.1	PAI-guided NIR-II PTT of 4T1 tumor
CP18 (TBZ-based CP)	1064	N.A.	Vascular imaging

IID-based CPs

IID is an isomer of a natural dye indigo, which can be quantitatively synthesized by oxindole and isatin in acetic acid in the presence of hydrochloric acid as a catalyst. IID is a versatile acceptor for constructing conjugated SMs and CPs in the fields of OSCs and OFETs. Some NIR-I phototheranostic IID-based SMs have ever been reported, however, IID-based CPs that absorb NIR-II light still need to be explored.

Wei et al. used an IID derivative AcIID as an acceptor to copolymerize with another acceptor diketopyrrolopyrrole (DPP) and thiophene donor to give CP1, which was then prepared to CP1-based ONAs. Interestingly, CP1-based ONAs have an olivary morphology with an average hydrodynamic size of 210 ± 15 nm (Figure ). With a PTCE of 49.5% in NIR-II, CP1-based ONAs show a great NIR-II PTT antitumor effect on HeLa cells (Figure ). Further in vivo NIR-II PTT against the HeLa tumor was also achieved as shown in Figure . Inspired by the strong electron-withdrawing ability of IID, another IID derivative of thieno-isoindigo was incorporated with a bithiophene donor to get CP2 by Cao et al. The as-prepared CP2-based ONAs exhibit strong absorption in the NIR-II region, which gives rise to a high PTCE of 66.4% (Figure ). Such fascinating properties endow CP2-based ONAs with highly efficient NIR-II PTT of MDA-MB-231 tumor under the guidance of PAI (Figure ). With an identical main chain structure to CP2 but slightly modified side chains, CP3 was developed for PAI-guided NIR-II PTT of the HeLa tumor by Sun et al. A new donor of 4,4-bisoctyl-4H-silolo[3,2-b:4,5- b′]dithiophene (DTS) was introduced by Wei et al. to form CP4 with thieno-isoindigo. CP4-based ONAs featured a broad absorption covering both the NIR-I and NIR-II regions. Likewise, CP4-based ONAs are potent material for NIR-II PTT of the HeLa tumor. Very recently, Jiang et al. integrated polycyclic, auxochromic, and coplanar effects together into a conjugated backbone to afford IID-based CP5. The largely fused acceptor in CP5 results in its profound NIR-II absorption, and the NIR-II PTCE of CP5-based ONAs is as high as 72.9%. Based on CP5-based ONAs, PAI-guided NIR-II PTT of the 4T1 tumor was successfully achieved (Figure ).

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TQL-based CPs

TQL acceptor is an annulated structure by integrating of benzothiadiazole (BT) and quinoxaline (QU). The improved electron-withdrawing ability of TQL suggests that it is an ideal building block for CPs with NIR-II absorption. Existing TQL-based CPs are suitable for ambipolar OFETs. We herein give some typical examples of TQL-based CPs for NIR-II phototheranostics.

Benzodithiophene (BDT) is the most common donor combined with TQL acceptor for NIR-II absorbing TQL-based CPs synthesis. CP6, CP7, and CP8 are such kinds of CPs for different applications. CP6-based ONAs show sufficient accumulation in the brain tumor upon intravenous injection, thereby realizing efficient PAI-guided NIR-II PTT of the U87 tumor (Figure ). In addition to tumor imaging, NIR-II absorbing ONAs enabled PAI, which can also be applied in stem cell tracking as pioneered by Yin et al. They synthesized a narrow bandgap CP7 and prepared CP7-based ONAs. These ONAs are ~100 nm-sized spherical nanoparticles visualized by TEM (Figure ). A strong PA signal of CP7-based ONAs can be observed in the NIR-II region due to their abundant absorption in this region (Figure ). The human mesenchymal stem cells (hMSCs) can be tracked by CP7-based ONAs through both NIR-I (860 nm) and NIR-II (1064 nm) PAI, however, NIR-II PAI provides a much improved contrast because of the deeper tissue penetration of NIR-II light (Figure ). Unlike the alkyl/alkoxyl substituted TQL used in previous studies, Zha et al. synthesized novel CP8 using an ester-substituted TQL. This study reveals that the repeating unit of CP8 has a large dihedral angle and narrow adiabatic energy as well as low radiative decay, which is responsible for the strongly electron-deficient property of this acceptor. CP8-based ONAs with twisted intramolecular charge transfer (TICT) character exhibit a high NIR-II PTCE of 61.6% and favorable PAI tracking of in situ hepatic tumor growth for over 20 days. Except for BDT, some other donors, such as oligothiophenes, also have been exploited in TQL-based CPs construction. As an example, CP9 was reported by Song et al., which was encapsulated into a PS–PEG matrix to form CP9-based ONAs with excellent NIR-II PTT effect on MDA-MB-231 tumor. Moreover, TQL is capable of copolymerizing with other acceptors, such as DPP. Two examples of CP10 and CP11 were reported by the same group. In the earlier report, CP10-based ONAs absorb both the NIR-I (750 nm) and NIR-II (1064 nm) light, and vascular PAI under both wavelengths was conducted. The results suggest a deeper tissue penetration of NIR-II light and PAI with higher SNR in NIR-II. Later, they further developed a random copolymer, CP11, and strong acceptors of DPP and TQL in the polymer backbone impart high absorptivity in NIR-I (808 nm) and NIR-II (1064 nm) to CP11. A systematic comparative photothermal heating study between NIR-I and NIR-II was conducted to prove the superior heating capability of the NIR-II laser at high depth (Figure ). Finally, the 4T1 tumor was completely eradicated by NIR-II PTT of CP11-based ONAs (Figure ).

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BBT-based CPs

As a classic acceptor with a hypervalent sulfur atom in its backbone, BBT featured a quite strong electron-deficient property. Moreover, BBT displays a quinone structure that contributes to electron delocalization and narrow bandgap. Fluorescent BBT-based SMs and CPs have shown their potential in OLEDs and FLI in earlier studies.

As mentioned in Section , BBT has already been incorporated with some donors for D–A conjugated SMs. This section includes some BBT-based CPs for NIR-II phototheranostics. Like TQL, BBT can also copolymerize with BDT for a variety of CPs. Chen et al. developed CP12-based ONAs derived from BBT and BDT, which were successfully used in NIR-II PAI-guided rheumatoid arthritis (RA) therapy (Figure ). The NIR-II PAI depth of CP12-based ONAs reaches 1.5 cm (Figure ). After intravenous injection of CP12-based ONAs, ultrasound (US) imaging and PAI of paw in the RA model were clearly visualized, under which the RA therapy could be guided (Figure ). By further inserting thiophene bridge into the polymer backbone between BBT and BDT, CP13 was synthesized by Guo et al. CP13-based ONAs were modified with an active targeting ligand cyclo(Arg-Gly-Asp-D-Phe-Lys(mpa)) (c-RGD) to give these nanoagents active tumor-targeting capability. Through intravenous injection of CP13-based ONAs, U87 tumor was treated by PAI-guided NIR-II PTT. This is the first active ligand decorated NIR-II absorbing CP-based ONAs capable of efficient phototheranostics of brain tumor. Biodegradability is a critical issue for the development of phototheranostic nanoagents. Although ONAs have much improved biocompatibility compared to their inorganic counterparts, they are not truly biodegradable. Therefore, designing and synthesizing of inherently biodegradable ONAs is of great significance but challenging. Jiang et al. prepared CP14-based ONAs with high NIR-II PTCE of 53% and bright NIR-II PA signal. More importantly, these ONAs metabolized under physiological conditions (Figure ). The biodegradation of CP14-based ONAs was demonstrated in vitro by the UV–Vis spectrum (Figure ). Further in vivo study by FLI of the mice after intravenous injection of CP14-based ONAs indicates the metabolism of these ONAs by means of the enhanced fluorescence intensity originates from the fluorescent small molecular fragments (Figure ). After intravenous injection, CP14-based ONAs mainly accumulated in the liver and spleen due to the size effect (>20 nm). The maximum fluorescence signals from blood, urine, liver, and feces were detected at 1 day, 2 days, 4 days, and 5 days, respectively, post-injection of CP14-based ONAs. These results not only validate the degradation of CP14-based ONAs in vivo but also indicate that the degradation products could be cleared out from living mice via both hepatobiliary and renal excretions. With such good biodegradability, CP14-based ONAs are preferable nanoagents for NIR-II PAI of tumor and vasculature. This study provides some molecular design principles toward metabolizable phototheranostic CP-based ONAs in NIR-II. Other donors, such as DTS, were subsequently introduced into CP synthesis. For example, Wei et al. synthesized CP15 bearing DTS donor and BBT acceptor with thiophene as π-bridge. They used CP15-based ONAs to perform PAI-guided NIR-II PTT of HepG-2 tumor. Additionally, BBT can copolymerize with two different donors to afford random terpolymers. Using BBT as the acceptor, bithiophene and BDT as the donors, a random terpolymer CP16 was reported by Sun et al. and CP16-based ONAs are high performance nanoagents for NIR-II PTT of orthotopic liver cancer.

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TBZ-based CPs

TBZ is a BBT-analogous acceptor by replacing one of the sulfur atoms in BBT with a nitrogen atom. In contrast to BBT, the central nitrogen atom in TBZ can be installed with alkyl chains to modulate the solution processability of TBZ-based CPs. Previous works show that TBZ-based CPs are appealing materials for thin film transistors with high hole mobilities. However, there are very few studies of TBZ-based CPs for NIR-II phototheranostics.

One representative TBZ-based CP of CP17 was reported by Men et al. in 2020. Owing to the strong electron-withdrawing capability of TBZ, the absorption of CP17-based ONAs extends to NIR-II region. With a high PTCE of 53.1% in NIR-II and amplified PA effect, CP17-based ONAs achieved PAI-guided NIR-II PTT of 4T1 tumor (Figure ). Another TBZ-based CP of CP18 with an identical backbone structure to CP17 but slightly modified side chains was synthesized by Guo et al. Unlike the conventional nanoprecipitation method, they used microfluidics to prepare uniform CP18-based ONAs for high-resolution three-dimensional (3D) NIR-II PAI of vasculatures (Figure ). This unique microfluidics method makes it possible to prepare ONAs in a controlled manner with high reproducibility in large scale. Therefore, the property difference of ONAs is minimized from batch to batch, which is beneficial for their further applications.

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CONCLUSIONS AND PERSPECTIVES

In conclusion, we have summarized the recent advances of ONAs based on SMs and CPs for NIR-II PAI and PTT. Compared with inorganic materials, ONAs are more biocompatible and their optical properties can be easily tuned. Despite the satisfactory theranostic outcome of ONAs, some problems and challenges remain and need to be overcome in future studies.

First, unlike NIR-I building blocks for ONAs, the number of NIR-II building blocks is quite limited. Chemists and material scientists should dedicate themselves to exploiting more building blocks for NIR-II ONAs either through chemically modifying existing units or through synthesizing totally new ones.

Second, studies of the relationship between the chemical structure of SMs/CPs and their PAI/PTT performance are lacking. It is necessary to establish a basic rule that could be used to guide the design and synthesis of high-performance NIR-II phototheranostic ONAs.

Third, tumor accumulation of NIR-II ONAs is realized by passive targeting at present, which may cause their inevitable accumulation in normal tissues. ONAs with active targeting capability should be further prepared through synthesizing inherent targeting SMs/CPs or post-modifying the ONAs for better phototheranostic efficacy. Another promising strategy to improve the targeting efficiency is the utilization of the so called “stimuli-responsive ONAs.” As a representative example, Li et al. developed a dual pH/viscosity activatable SM LET-1052, whose NIR-II PTT effect was triggered in an acidic tumor microenvironment (TME). More importantly, LET-1052 was able to evaluate the PTT efficacy in real-time through the enhanced fluorescence due to the increased intracellular viscosity caused by cellular death. Though there have been some achievements, this strategy needs rational molecular design and remains a huge challenge.

Fourth, the biosafety of NIR-II ONAs is a big issue. Although a few pioneering works have shown some ONAs with biodegradability, their underlying degradation mechanism and systemic toxicity are not well understood. Further efforts should be devoted to exploring the long-term biosafety of NIR-II ONAs regarding the degradation mechanism and metabolic pathway.

These problems and challenges need to be addressed urgently, however, they are hard tasks. Through cooperation of researchers in nanotechnology, chemistry, and materials science, there will be possible solutions, thereby accelerating the clinical translation of NIR-II phototheranostic ONAs.

ACKNOWLEDGEMENT

This work was supported by the Postdoctoral Fund of Westlake University (103110126582102).

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

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