Second near-infrared photothermal therapy (NIR-II PTT, 1000-1500 nm) has recently emerged as a new phototherapeutic modality with the advantages of deeper penetration, less energy dissipation and minimal normal-tissue toxicity over traditional first NIR PTT (750-1000 nm). However, suboptimal photothermal conversion and limited therapeutic efficacy remain the major challenges for NIR-II PTT. With the convergence in materials science, nanomedicine and biology, multifunctional NIR-II photothermal inorganic or organic materials have been extensively developed to combine NIR-II PTT with other therapeutic modalities for improved efficacies in treating life-threatening diseases including cancer and infection. This review summarizes the recent advances of NIR-II photothermal combinational theranostics pertinent to chemotherapy, immunotherapy, radiotherapy, and photodynamic, sonodynamic, chemodynamic, gene, gas, ionic, vascular and magnetothermal therapy. Potential obstacles and perspectives for future research and clinical translation of this new theranostic modality are also discussed.

Second near-infrared photothermal materials for combinational nanotheranostics

Nanotheranostics is one of the biggest scientific breakthroughs in nanomedicine. Most of the currently available diagnosis and therapies are invasive, time-consuming, and associated with severe toxic side effects. Nanotheranostics, on the other hand, has the potential to bridge this gap by harnessing the capabilities of nanotechnology and nanomaterials for combined therapeutics and diagnostics with markedly enhanced efficacy. However, nanomaterial applications in nanotheranostics are still in its infancy. This is due to the fact that each disease has a particular microenvironment with well-defined characteristics, which promotes deeper selection criteria of nanomaterials to meet the disease needs. In this review, we have outlined how nanomaterials are designed and tailored for nanotheranostics of cancer and other diseases such as neurodegenerative, autoimmune (particularly on rheumatoid arthritis), and cardiovascular diseases. The penetrability and retention of a nanomaterial in the biological system, the therapeutic strategy used, and the imaging mode selected are some of the aspects discussed for each disease. The specific properties of the nanomaterials in terms of feasibility, physicochemical challenges, progress in clinical trials, its toxicity, and their future application on translational medicine are addressed. Our review meticulously and critically examines the applications of nanotheranostics with various nanomaterials, including graphene, across several diseases, offering a broader perspective of this emerging field.

/pdf/nanomaterials-for-nanotheranostics-tuning-their-properties-1zx0ujzzzk.pdf

Nanomaterials for Nanotheranostics: Tuning Their Properties According to Disease Needs.

Nanotheranostic agents of gold nanomaterials in the second near-infrared (NIR-II) window have attracted significant attention in cancer management, owing to the reduced background signal and deeper penetration depth in tissues. However, it is still challenging to modulate the localized surface plasmon resonance (LSPR) of gold nanomaterials from the first near-infrared (NIR-I) to NIR-II region. Herein, a plasmonic modulation strategy of gold nanorods (GNRs) through manganese dioxide coating is developed for NIR-II photoacoustic/magnetic resonance (MR) duplex-imaging-guided NIR-II photothermal chemodynamic therapy. GNRs are coated with silica dioxide (SiO2 ) and then covered with magnesium dioxide (MnO2 ) to obtain the final product of GNR@SiO2 @MnO2 (denoted as GSM). The LSPR peak of GNRs could be tuned by adjusting the thickness of the MnO2 layer. Theoretical simulations reveal that this plasmonic modulation is mainly due to the change of refraction index around the GNRs after coating with the MnO2 layer. Additionally, the MnO2 layer is demonstrated to degrade into Mn2+ ions in response to peroxide and acidic protons in the tumor microenvironment, which allows for MR imaging and chemodynamic therapy. This plasmonic modulation strategy can be adapted to other metal nanomaterials and the construction of a new class of NIR-II nanotheranostics.

Manganese‐Dioxide‐Coating‐Instructed Plasmonic Modulation of Gold Nanorods for Activatable Duplex‐Imaging‐Guided NIR‐II Photothermal‐Chemodynamic Therapy

Gold nanorods (NRs), pseudo-one-dimensional rod-shaped nanoparticles (NPs), have become one of the burgeoning materials in the recent years due to their anisotropic shape and adjustable plasmonic properties. With the continuous improvement in synthetic methods, a variety of materials have been attached around Au NRs to achieve unexpected or improved plasmonic properties and explore state-of-the-art technologies. In this review, we comprehensively summarize the latest progress on Au NRs, the most versatile anisotropic plasmonic NPs. We present a representative overview of the advances in the synthetic strategies and outline an extensive catalogue of Au-NR-based heterostructures with tailored architectures and special functionalities. The bottom-up assembly of Au NRs into preprogrammed metastructures is then discussed, as well as the design principles. We also provide a systematic elucidation of the different plasmonic properties associated with the Au-NR-based structures, followed by a discussion of the promising applications of Au NRs in various fields. We finally discuss the future research directions and challenges of Au NRs.

Gold Nanorods: The Most Versatile Plasmonic Nanoparticles

Brain tumor is one of the most lethal cancers owing to the existence of blood-brain barrier and blood-brain tumor barrier as well as the lack of highly effective brain tumor treatment paradigms. Herein, cyclo(Arg-Gly-Asp-D-Phe-Lys(mpa)) decorated biocompatible and photostable conjugated polymer nanoparticles with strong absorption in the second near-infrared (NIR-II) window are developed for precise photoacoustic imaging and spatiotemporal photothermal therapy of brain tumor through scalp and skull. Evidenced by the higher efficiency to penetrate scalp and skull for 1064 nm laser as compared to common 808 nm laser, NIR-II brain-tumor photothermal therapy is highly effective. In addition, via a real-time photoacoustic imaging system, the nanoparticles assist clear pinpointing of glioma at a depth of almost 3 mm through scalp and skull with an ultrahigh signal-to-background ratio of 90. After spatiotemporal photothermal treatment, the tumor progression is effectively inhibited and the survival spans of mice are significantly extended. This study demonstrates that NIR-II conjugated polymer nanoparticles are promising for precise imaging and treatment of brain tumors.

Through Scalp and Skull NIR-II Photothermal Therapy of Deep Orthotopic Brain Tumors with Precise Photoacoustic Imaging Guidance

The miniaturization of gold nanorods exhibits a bright prospect for intravital photoacoustic imaging (PAI) and the hollow structure possesses a better plasmonic property. Herein, miniature hollow gold nanorods (M-AuHNRs) (≈46 nm in length) possessing strong plasmonic absorbance in the second near-infrared (NIR-II) window (1000-1350 nm) are developed, which are considered as the most suitable range for the intravital PAI. The as-prepared M-AuHNRs exhibit 3.5 times stronger photoacoustic signal intensity than the large hollow Au nanorods (≈105 nm in length) at 0.2 optical density under 1064 nm laser irradiation. The in vivo biodistribution measurement shows that the accumulation in tumor of miniature nanorods is twofold as high as that of the large counterpart. After modifying with a tumor-targeting molecule and fluorochrome, in living tumor-bearing mice, the M-AuHNRs group gives a high fluorescence intensity in tumors, which is 3.6-fold that of the large ones with the same functionalization. Moreover, in the intravital PAI of living tumor-bearing mice, the M-AuHNRs generate longer-lasting and stronger photoacoustic signal than the large counterpart in the NIR-II window. Overall, this study presents the fabrication of M-AuHNRs as a promising contrast agent for intravital PAI.

Miniature Hollow Gold Nanorods with Enhanced Effect for In Vivo Photoacoustic Imaging in the NIR‐II Window

The strategy that combines photodynamic therapy (PDT) and photothermal therapy (PTT) is widely used to achieve strong antitumor efficiency. Since light in the NIR-II window possesses ideal penetration ability, developing NIR-II PTT and NIR-II light triggered photosensitizer release for combined PDT and PTT is very promising in nanomedicine. Methods: We develop a novel nanocarrier (termed AuHNRs-DTPP) by conjugating photosensitizer contained chimeric peptide (DTPP) to Au hollow nanorods (AuHNRs). AuHNRs was obtained by a Te-templated method with the assistance of L-cysteine. The chimeric peptide PpIX-PEG8-GGK(TPP)GRDEVDGC (DTPP) was obtained through a solid-phase peptide synthesis (SPPS) method. Results: Under the 1064 nm laser irradiation, the nanocarrier can accumulate heat quickly for efficient PTT, and then release activated photosensitizer for real-time apoptosis imaging. Thereafter, supplementary PDT can be conducted to kill tumor cells survived from the PTT, and meanwhile the normal tissue can be protected from photo-toxicity. Conclusion: This designed AuHNRs-DTPP nanocarrier with remarkable therapy effect, real-time apoptosis imaging ability and reduced skin damage is of great potential in nanomedicine application.

Au Hollow Nanorods-Chimeric Peptide Nanocarrier for NIR-II Photothermal Therapy and Real-time Apoptosis Imaging for Tumor Theranostics.

Chemodynamic therapy (CDT) destroys cancer cells by converting H2O2 or O2 into reactive oxygen species (ROS), but its therapeutic efficacy is restricted by the antioxidant capacity of tumor. Previous solutions focused on strengthening the nanodrugs with the ability to increase ROS production or weaken the antioxidant capacity of cancer cells. Conversely, we here develop a mild nanodrug with negligible side effects. Specifically, the Au@Pt nanozyme decorated on a bacterial surface (Bac-Au@Pt) is reported to achieve precise CDT. Due to the tumor targeting ability of bacteria and catalytic property of Au@Pt nanozyme under acidic conditions, this nanosystem can release ROS to tumor cells effectively. In addition, the interferon gamma released by T cells specifically decreases the intracellular reductants in tumor cells, while having no obvious effect on normal cells. Therefore, a low dose of Bac-Au@Pt achieves a satisfactory therapeutic efficacy to tumor cells and is nontoxic to normal cells even at their acidic components. This nanosystem enables CDT and immunotherapy to mutually benefit and improve by each other, providing a promising strategy to achieve high anticancer efficacy even with a low dose usage.

Precise Chemodynamic Therapy of Cancer by Trifunctional Bacterium-Based Nanozymes.

Bacteria show promise for use in the field of combination cancer therapy because of their abilities to accumulate in tumors and their roles as natural immunologic adjuvants. However, the huge size of bacteria decreases their chances of being delivered into tumor cells. Moreover, their toxins may cause systemic toxicity in living organisms. Here, we proposed a method to in situ synthesize Au nanoparticles on the surface of Escherichia coli (E. coli), followed by sonication to acquire Au nanoparticles loaded membrane nanosheets (AuMNs) for use in photothermal and combination cancer therapy. Compared to E. coli-loaded Au nanoparticles (E. coli@Au), the small size of membrane nanosheets can be successfully delivered into tumor cells. In addition, the enrichment of AuMNs in tumor site is significantly enhanced via EPR effect, facilitating to activate photothermal conversion under 808 nm laser. Besides, the function of bacteria as natural immunologic adjuvants to promote anti-PD-L1 efficacy is still retained in AuMNs, while the inflammation and damage to viscera caused by AuMNs were milder than E. coli@Au. This study aims to decrease the systemic toxicity of bacteria and promote anti-PD-L1 efficacy in bacteria-mediated combination therapy, so as to open up a new avenue for drug delivery via natural processes.

Biogenic Hybrid Nanosheets Activated Photothermal Therapy and Promoted Anti-PD-L1 Efficacy for Synergetic Antitumor Strategy

Bladder cancer (BC) occurs in the urinary system which has high incidence and mortality. During past decades, lots of long noncoding RNAs (lncRNAs) have been identified to function in cancer progression, including BC. In our research, we targeted at investigating the functions and mechanisms of lncRNA pro-transition associated RNA (PTAR) in BC. Functional assays were implemented to access the changes of BC cell phenotype. Mechanistic assays were applied for confirming the interaction between RNAs. Based on the collected data, PTAR expression was high in BC cells and silenced PTAR repressed BC cell proliferative, migratory and invasive abilities but improved cell apoptotic ability. In vivo study also verified PTAR depletion inhibited BC tumor growth. Furthermore, miR-299-3p was confirmed to bind with PTAR and its overexpression suppressed malignant behaviors of BC cells. Cluster of differentiation 164 (CD164) was proved to be miR-299-3p target. Rescue experiments implied overexpressed CD164 offset the inhibitory function of PTAR depletion on BC cell phenotype. Additionally, CD164 was uncovered to combine with C-X-C motif chemokine receptor 4 (CXCR4) to switch on PI3K/AKT pathway. To conclude, PTAR facilitates BC development via regulating miR-299-3p/CD164 axis and activating PI3K/AKT pathway. 

Xuyu Li

Papers

Miniature Hollow Gold Nanorods with Enhanced Effect for In Vivo Photoacoustic Imaging in the NIR‐II Window

Au Hollow Nanorods-Chimeric Peptide Nanocarrier for NIR-II Photothermal Therapy and Real-time Apoptosis Imaging for Tumor Theranostics.

Precise Chemodynamic Therapy of Cancer by Trifunctional Bacterium-Based Nanozymes.

Biogenic Hybrid Nanosheets Activated Photothermal Therapy and Promoted Anti-PD-L1 Efficacy for Synergetic Antitumor Strategy

LncRNA PTAR activates the progression of bladder cancer by modulating miR-299-3p/CD164 axis.