Efficient Photothermal Agents Research Articles

Bismuth@Bismuth Sulfide Core@Shell Structure for Near Infrared II Light Triggered Photothermal Therapy

AbstractNear infrared (NIR) light, especially NIR‐II, triggered photothermal therapy has gained increasing attention due to its deep tissue penetration ability. The development of new NIR‐II photothermal agent may accelerate the clinical translation. As a semiconductor, bismuth (Bi) can be activated by NIR‐II light. Herein, we developed Bi@bismuth sulfide (Bi2S3) core@shell nanoparticles (NPs) as new NIR‐II triggered PTA. The photothermal conversion efficiency of Bi@Bi2S3 NPs was calculated to be 48.39 %. With 1064 nm laser irradiation, Bi@Bi2S3 NPs could effectively induce temperature elevation and kill cancer cells. In vivo experiments further prove that Bi@Bi2S3 NPs can serve as an efficient photothermal agent with well biocompatibility for tumor elimination.

Synchronously manipulating absorption and nonradiative transition of croconaine via donor engineering for efficient NIR-II photothermal theranostics

Organic molecules with strong absorption in the near-infrared (NIR)-II region are highly desired for cancer photothermal theranostics. However, it remains challenges to construct NIR-II photothermal agents with desired optical properties. This study reports a donor engineering approach to simultaneously manipulate the absorption and nonradiative transitions of croconaine dyes. By introducing different donor units with increasing electron donating ability to the backbone, the absorption of the synthesized croconaines were gradually red-shifted to NIR-II region, especially the benzo[c,d]indolium conjugated croconaine (CR1045). The extensive conjugation of CR1045 had a narrower HOMO-LUMO energy gap and strong NIR-II light responsiveness. Importantly, the steric repulsion between this large planar donor and croconate acceptor of CR1045 promotes the formation of a twisted intramolecular charge transfer (TICT) state, making it more prone to direct the absorbed energy towards heat-producing non-radiative decay rather than other dissipative pathways. And the nanoformulated CR1045 exhibits excellent optoacoustic generation capability and ultrahigh photothermal conversion efficiency (∼84%). In vitro and in vivo investigations confirm good optoacoustic imaging and effective photothermal treatment of tumors. Therefore, this work offers insights into donor regulation for the future development of efficient NIR-II photothermal agents.

Chaotropic Effect-Induced Self-Assembly of the Malachite Green and Boron Cluster for Toxicity Regulation and Photothermal Therapy.

Malachite green (MG), a toxic antibacterial agent, is widely used in the farming industry. Effectively regulating the biotoxicity of this highly water-soluble cationic dye is challenging. Here, we present a novel strategy to reduce the biotoxicity of MG through the self-assembly of MG and the closo-dodecaborate cluster ([B12H12]2-) driven by the chaotropic effect. [B12H12]2- and MG in an aqueous solution can rapidly form an insoluble cubic-type supramolecular complex (B12-MG), and the original toxicity of MG is completely suppressed. Surprisingly, this supramolecular complex, B12-MG, has a strong UV-vis absorption peak at 600-800 nm and significant photothermal conversion efficiency under 660 nm laser irradiation. On this basis, B12-MG, the supramolecular complex, can be used as an efficient photothermal agent for antimicrobial photothermal therapy (PTT) both in vitro and in vivo. As a molecular chaperone of MG, [B12H12]2- not only can be applied as an antidote to regulate the biotoxicity of MG but also provides a novel method for the construction of photothermal agents for PTT based on the chaotropic effect.

NIR-dye bridged human serum albumin reassemblies for effective photothermal therapy of tumor

Human serum albumin (HSA) based drug delivery platforms that feature desirable biocompatibility and pharmacokinetic property are rapidly developed for tumor-targeted drug delivery. Even though various HSA-based platforms have been established, it is still of great significance to develop more efficient preparation technology to broaden the therapeutic applications of HSA-based nano-carriers. Here we report a bridging strategy that unfastens HSA to polypeptide chains and subsequently crosslinks these chains by a bridge-like molecule (BPY-Mal2) to afford the HSA reassemblies formulation (BPY@HSA) with enhanced loading capacity, endowing the BPY@HSA with uniformed size, high photothermal efficacy, and favorable therapeutic features. Both in vitro and in vivo studies demonstrate that the BPY@HSA presents higher delivery efficacy and more prominent photothermal therapeutic performance than that of the conventionally prepared formulation. The feasibility in preparation, stability, high photothermal conversion efficacy, and biocompatibility of BPY@HSA may facilitate it as an efficient photothermal agents (PTAs) for tumor photothermal therapy (PTT). This work provides a facile strategy to enhance the loading capacity of HSA-based crosslinking platforms in order to improve delivery efficacy and therapeutic effect.

3D modeling of in vivo MRI-guided nano-photothermal therapy mediated by magneto-plasmonic nanohybrids

BackgroundNano-photothermal therapy (NPTT) has gained wide attention in cancer treatment due to its high efficiency and selective treatment strategy. The biggest challenges in the clinical application are the lack of (i) a reliable platform for mapping the thermal dose and (ii) efficient photothermal agents (PTAs). This study developed a 3D treatment planning for NPTT to reduce the uncertainty of treatment procedures, based on our synthesized nanohybrid.MethodsThis study aimed to develop a three-dimensional finite element method (FEM) model for in vivo NPTT in mice using magneto-plasmonic nanohybrids, which are complex assemblies of superparamagnetic iron oxide nanoparticles and gold nanorods. The model was based on Pennes' bio-heat equation and utilized a geometrically correct mice whole-body. CT26 colon tumor-bearing BALB/c mice were injected with nanohybrids and imaged using MRI (3 Tesla) before and after injection. MR images were segmented, and STereoLithography (STL) files of mice bodies and nanohybrid distribution in the tumor were established to create a realistic geometry for the model. The accuracy of the temperature predictions was validated by using an infrared (IR) camera.ResultsThe photothermal conversion efficiency of the nanohybrids was experimentally determined to be approximately 30%. The intratumoral (IT) injection group showed the highest temperature increase, with a maximum of 17 °C observed at the hottest point on the surface of the tumor-bearing mice for 300 s of laser exposure at a power density of 1.4 W/cm2. Furthermore, the highest level of tissue damage, with a maximum value of Ω = 0.4, was observed in the IT injection group, as determined through a simulation study.ConclusionsOur synthesized nanohybrid shows potential as an effective agent for MRI-guided NPTT. The developed model accurately predicted temperature distributions and tissue damage in the tumor. However, the current temperature validation method, which relies on limited 2D measurements, may be too lenient. Further refinement is necessary to improve validation. Nevertheless, the presented FEM model holds great promise for clinical NPTT treatment planning.

Upconversion nanoparticles@single-walled carbon nanotubes composites as efficient self-monitored photo-thermal agents

Conventional photothermal therapy (PTT) usually relies on a macroscopic heat source to raise the temperature of tissues to 41–45 °C, which not only kills the pathological cells but causes severe side effects on nearby normal tissues, thus reducing the accuracy of PTT. Here we successfully fabricated nanocomposites of NaYF4:Yb3+,Tm3+@NaYF4:Yb3+@SiO2-SWCNTs, in which the upconversion nanoparticles (UCNPs) serve as real-time temperature-feedback moiety and the single-walled carbon nanotubes (SWCNTs) serve as efficient nano-heaters. The sample displays an excellent photothermal conversion capacity, i.e., the temperature of the aqueous dispersion increases from 23.3 °C up to 60.1 °C under 980 nm excitation due to the intense absorption and highly efficient heat generation of SWCNTs. Meanwhile, the temperature of the nanocomposites is monitored in real time based on the fluorescent intensity ratio of UCNPs. The in-vitro experiments demonstrate that the temperature of the nanocomposites at tissue injection of 1 mm can reach PTT temperature of 42.2 °C with a facile surrounding temperature of 36.2 °C under moderate laser power (980 nm, 2.0 W cm−2). These results provide a novel design for multifunctional nanocomposites that enable safe and controlled PTT.

Oxygen vacancy engineering of TiO2 nanosheets for enhanced photothermal therapy against cervical cancer in the second near-infrared window

Cervical cancer is the most common and deadly female cancer on the worldwide scale. Considering that the conventional surgery treatment and chemotherapy would cause certain side effects, photothermal therapy (PTT) possesses desired therapeutic efficiency and insignificant side effects against cervical cancer. However, the lack of efficient and safe photothermal agents that operate in the second near-infrared (NIR-II) window is a main obstacle hindering the clinical transformation of PTT. Titanium dioxide (TiO2)-based nanomaterials are commonly applied in the biomedicine field, but the weak absorption and low photothermal conversion efficiency (PCE) of TiO2 in the NIR region limit their applications in PTT. Herein, we report the oxygen vacancy engineering that is a robust strategy to regulate the electronic structures of TiO2 for photothermal conversion properties optimizing. The obtained oxygen vacancy-doped TiO2−x nanosheets exhibit strong NIR-II absorption and high PCE owing to their decreased bandgap. Specifically, the PCE of TiO2−x nanosheets is determined to be 69.5 % in the efficient NIR-II window, which is much higher than that of widely reported PTT agents. Complete tumor recession without recurrence or pulmonary metastasis is realized by enhanced NIR-II PTT via TiO2−x nanosheets at an ultralow and safe laser exposure (0.6 W/cm2). Our findings suggest that oxygen vacancy engineering of nanomaterials could regulate their photothermal conversion performances, promoting the further application of TiO2-based nanomaterials in the biomedical.

Functionalization of and through Melanin: Strategies and Bio-Applications.

A unique feature of nanoparticles for bio-application is the ease of achieving multi-functionality through covalent and non-covalent functionalization. In this way, multiple therapeutic actions, including chemical, photothermal and photodynamic activity, can be combined with different bio-imaging modalities, such as magnetic resonance, photoacoustic, and fluorescence imaging, in a theragnostic approach. In this context, melanin-related nanomaterials possess unique features since they are intrinsically biocompatible and, due to their optical and electronic properties, are themselves very efficient photothermal agents, efficient antioxidants, and photoacoustic contrast agents. Moreover, these materials present a unique versatility of functionalization, which makes them ideal for the design of multifunctional platforms for nanomedicine integrating new functions such as drug delivery and controlled release, gene therapy, or contrast ability in magnetic resonance and fluorescence imaging. In this review, the most relevant and recent examples of melanin-based multi-functionalized nanosystems are discussed, highlighting the different methods of functionalization and, in particular, distinguishing pre-functionalization and post-functionalization. In the meantime, the properties of melanin coatings employable for the functionalization of a variety of material substrates are also briefly introduced, especially in order to explain the origin of the versatility of melanin functionalization. In the final part, the most relevant critical issues related to melanin functionalization that may arise during the design of multifunctional melanin-like nanoplatforms for nanomedicine and bio-application are listed and discussed.

Rodlike nanomaterials from organic diradicaloid with high photothermal conversion capability for tumor treatment

AbstractOrganic diradicaloids with unique open‐shell structures and properties have been widely used in organic electronics and spintronics. However, their advantageous optical properties have been explored less in the biomedical field. In this work, the photothermal conversion behaviors of a boron‐containing organic diradicaloid (BOD) are reported. BOD can assemble with 1,2‐distearoyl‐sn‐glycero‐3‐phosphoethanolamine‐poly(ethylene glycol) to form rodlike nanoparticles (BOD NPs). These as‐prepared BOD NPs exhibit high photothermal conversion capability and robust photothermal stability. Notably, they possess morphological superiority, which guarantees the effective photothermal therapy of tumors. This work thus demonstrates the promise of organic diradicaloids as efficient photothermal agents for biomedical applications.

Near Infrared-Absorbing Nanoparticle-Mediated Endovascular Photothermal Precision Embolization of Tumor Feeding Vessels for Starvation Treatment.

Photothermal therapy has attracted enormous attention as an efficient treatment modality in cancer ablation but still encounters a major bottleneck due to the limited penetration depth of light inside tissues. To overcome the challenge of deep tissue penetration, we present a strategy of endovascular photothermal precision embolization (EPPE), which employs an endovascular optical fiber to induce local embolization only in the entrance of feeding vessels through photothermal heating for the purpose of fully blocking the blood supply of the whole tumor. In EPPE, we apply a highly efficient and biocompatible photothermal agent, i.e., near-infrared (NIR)-light-absorbing diketopyrrolopyrrole-dithiophene-based nanoparticle, which exhibits a high cell-killing efficacy at a concentration of 200 μg/mL using 808 nm laser irradiation of 0.5 W/cm2 within 5 min in both 2D cell culture and a 3D tumor spheroid model. We verify the feasibility of EPPE in an ex vivo organ-structured recellularized liver model and further confirm the in vivo efficacy of the photothermal treatment in a rat liver model. The photothermal treatment combined with the embolization effect holds promise to serve as an effective starvation therapy to treat tumors of varying sizes and locations.

Multifunctional fluorescent mesoporous carbon nanoprobe for MMP-2-activated cancer cell imaging and targeted photothermal therapy

The integration of cancer imaging with therapy in a simple system is warranted for precise cancer therapy. In this study, carboxyl-functionalized mesoporous carbon nanospheres (MCN) which are efficient photothermal agents and excellent fluorescence quenchers, were used for cancer cell imaging and selective photothermal therapy (PTT) applications. Using MCN, a matrix metalloproteinase-2 (MMP-2)- responsive theranostic nanoprobe was generated by functionalizing an MMP-2-specific fluorescent-labeled PLGVR sequence on the surface of MCN. The nanoprobe not only can be used to detect MMP-2 with a low detection limit of 0.3 pg mL−1, but also can achieve the sensitive intracellular MMP-2 imaging in living cells, validating the differentiation of cancer cells from healthy cells based on the recovered fluorescence intensity. More importantly, selective cancer PTT was achieved using MMP-2-triggered cancer cell imaging. Our in vitro studies showed that by regulating the power density and irradiation time, the nanoprobe can effectively kill cancer cells via PTT. Our strategy opens new avenues for precision medicine, especially phototherapy.

Coiled-coil peptide-based assembly of a plasmonic core-satellite polymer-metal nanocomposite as an efficient photothermal agent for drug delivery applications

Polymer-metal nanocomposites have widespread applications in biomedical fields such as imaging, catalysis, and drug delivery. These particles are characterized by combined organic and inorganic properties. Specifically, photothermal nanocomposites incorporating polymeric and plasmonic nanoparticles (NPs) have been designed for both triggered drug release and as imaging agents. However, the usual design of nanocomposites confers characteristic issues, among which are the decrease of optical properties and resulting low photothermal efficiency, as well as interactions with loaded drugs. Herein, we report the design of a core-satellite polymer-metal nanocomposite assembled by coiled-coil peptides and its superior photothermal efficiency compared to electrostatic-driven nanocomposites which is the standard design. We also found that the orientation of gold nanorods on the surface of polymeric NPs is of importance in the final photothermal efficiency and could be exploited for various applications. Our findings provide an alternative to current wrapping and electrostatic assembly of nanocomposites with the help of coiled-coil peptides and an improvement of the control over core-satellite assemblies with plasmonic NPs. It paves the way to highly versatile assemblies due to the nature of coiled-coil peptides to be easily modified and sensitive to pH or temperature.

Excitation of quantum-sized (CuS)n clusters for NIR-II photothermal application: Insights from experiment and DFT calculation

Copper sulfide nanoclusters have an intensified and adaptable near infrared-II (NIR-II) light absorption due to their intriguing electronic structure, which endues them with a promising prospect for photothermal tumor-ablation in nanotherapy. In this study, quantum-sized (CuS)n with cluster-size-dependent distinctiveness of non-shifting, red-shifting, and blue-shifting absorption spectra under photo-excitation were studied experimentally and theoretically; three different stages categorized as molecule, nanocluster and nanoparticle were identified to delineate different mechanisms underlying photo-excitation. Addressing plasmonicity by hole-electron analysis based on time-dependent density functional theory (TD-DFT), we adapted TD-DFT protocol to measure the distribution, collectiveness and coherence of the excited molecular orbital pairs of (CuS)n. The current calculation can also lend weight to plasmonicity evaluation in other semiconducting alloy and compound nanomaterials. We ascertained the correlation of the optical properties of (CuS)n nanoclusters to enhanced plasmonicity arising from an excitonic-dominated excitation along with growing cluster size n, laying down foundations for precise and controllable applications of (CuS)n nanoclusters. In vivo tumor-ablating assessment of (CuS)n nanocluster preliminarily qualified it as an efficient low-dose photothermal transduction agent under a low NIR-II irradiance. This study provides a comprehensive view on (CuS)n nanoclusters preparation, excitation mechanism and application prospects besides uniqueness in methodology, shedding light on further application investigation and engineering for the light-functioning nanoclusters.

Enhanced photothermal therapy performance of D-A conjugated polymers based on [1,2,3]triazolo[4,5-g]quinoxaline by manipulating molecular motion.

Donor-acceptor (D-A) conjugated polymers can favor the nonradiative thermal dissipation process, due to the formation of an intramolecular charge transfer (ICT) state resulting from the electron cloud delocalization of the HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital). Thus, to realize a high extinction coefficient and excellent photothermal conversion ability for a single photothermal agent, donor-acceptor type conjugated polymers PBDT-QTz and PCDT-QTz, comprising a new electron-deficient unit 2-(2-decyltetradecyl)-6,7-dimethyl-2H-[1,2,3]triazolo [4,5-g] quinoxaline (QTz) as the acceptor and 4,8-di(thiophen-2-yl)benzo[1,2-b:4,5-b']dithiophene (BDT) or 4H-cyclopenta[2,1-b:3,4-b'] dithiophene (CDT) as the donor, are designed and synthesized by manipulating intramolecular motion. The high extinction coefficient of 28.5 L g-1 cm-1 at 850 nm and the optimal photothermal conversion efficiency of 64.3% under an 808 nm laser are achieved based on PBDT-QTz. Consequently, PBDT-QTz nanoparticles can be successfully used for both in vitro and in vivo experiments. After intravenous administration and 808 nm laser irradiation, HeLa tumor-bearing mice achieve complete tumor remission without recurrence. The results provide an efficient photothermal agent by manipulating molecular motion.

Au nanoparticles decorated nanographene oxide-based platform: Synthesis, functionalization and assessment of photothermal activity

A novel hybrid nanocomposite formed of carboxylated Nano Graphene Oxide (c-NGO), highly densely decorated by monodisperse citrate-coated Au nanoparticles (c-NGO/Au NPs), is synthesized and thoroughly characterized for photothermal applications. A systematic investigation of the role played by the synthetic parameters on the Au NPs decoration of the c-NGO platform is performed, comprehensively studying spectroscopic and morphological characteristics of the achieved nanostructures, thus elucidating their still not univocally explained synthesis mechanism.Remarkably, the Au NPs coating density of the c-NGO sheets is much higher than state-of-the-art systems with analogous composition prepared with different approaches, along with a higher NPs size dispersion. A novel theoretical approach for estimating the average number of NPs per sheet, combining DLS and TEM results, is developed. The assessment of the c-NGO/Au NPs photothermal activity is performed under continuous wave (CW) laser irradiation, at 532 nm and 800 nm, before and after functionalization with PEG-SH. c-NGO/Au NPs composite behaves as efficient photothermal agent, with a light into heat conversion ability higher than that of the single components. The c-NGO/Au NPs compatibility for photothermal therapy is assessed by in vitro cell viability tests, which show no significant effects of c-NGO/Au NPs, as neat and PEGylated, on cell metabolic activity under the investigated conditions. These results demonstrate the great potential held by the prepared hybrid nanocomposite for photothermal conversion technologies, indicating it as particularly promising platform for photothermal ablation of cancer cells.

Photothermal effects of gold nanorods in aqueous solution and gel media: Influence of particle size and excitation wavelength.

Gold nanorods (GNRs) have emerged as the most efficient photothermal agent in cancer therapy and photocatalysis. Understanding the influence of the surrounding medium, particle size, and excitation wavelength is critical to optimising the photothermal conversion rate. Here, three pairs of large and small gold nanorods of different aspect ratios and their heat generation under laser radiation at on and off surface plasmon resonance wavelengths in aqueous solution and gel-like media are investigated. In the aqueous solution, the temperature rise of the large gold nanorods is more than with small gold nanorods at resonance excitation. In contrast to the large gold nanorods (LGNRs), the small gold nanorods (SGNRs) were less sensitive to excitation wavelength. At off-resonance excitation, the temperature rise of the SGNRs is larger than that of the LGNRs. In the agarose gel, the photothermal effect of the SGNRs is greater than LGNRs excited at the wavelength near their solution phase longitudinal surface plasmon resonance wavelength. The temperature increase of LGNRs in gel is significantly less than in aqueous solution. These findings suggest that SGNRs could be more beneficial than the LGNRs for photothermal applications in biological systems and provides further insight when selecting GNRs.

Assessing the Efficiency of Triangular Gold Nanoparticles as NIR Photothermal Agents In Vitro and Melanoma Tumor Model.

Photothermal therapy (PTT) is gaining a lot of interest as a cancer treatment option with minimal side effects due to the efficient photothermal agents employed. They are based on nanomaterials that, upon laser irradiation, absorb photon energy and convert it into heat to induce hyperthermia, which destroys the cancer cells. Here, the unique light-to-heat conversion features of three different gold nanotriangular nanoparticles (AuNTs) are evaluated with respect to their absorption properties to select the most efficient nanoheater with the highest potential to operate as an efficient photothermal agent. AuNTs with LSPR response in- and out- of resonance with the 785 nm near-infrared (NIR) excitation wavelength are investigated. Upon 15 min laser exposure, the AuNTs that exhibit a plasmonic response in resonance with the 785 nm laser line show the highest photothermal conversion efficacy of 80%, which correlates with a temperature increase of 22 °C. These photothermal properties are well-preserved in agarose-based skin biological phantoms that mimic the melanoma tumoral tissue and surrounding healthy tissue. Finally, in vitro studies on B16.F10 melanoma cells prove by fluorescence staining and MTT assay that the highest phototoxic effect after NIR laser exposure is induced by AuNTs with LSPR response in resonance with the employed laser line, thus demonstrating their potential implementation as efficient photothermal agents in PTT.

Interfacial preparation of multi-branched magneto-plasmonic Fe3O4@Au core@shell nanocomposites as efficient photothermal agents for antibacterial application

We report the synthesis of multi-branched Fe3O4@Au core@shell nanocomposites through a template-free liquid-liquid interfacial growth reaction. The prepared magneto-plasmonic Fe3O4@Au core@shell nanocomposites exhibited outstanding SPR absorption in the NIR region, which imparts the nanocomposites with a superior photothermal conversion efficiency of 69.9%, making this material an efficient photothermal agent for antibacterial application. Our results indicated that the prepared Fe3O4@Au core@shell nanocomposites could effectively kill both Gram negative E. coli and Gram positive S. aureus under 980 nm laser irradiation and kept good photo-stability after multiple photothermal bacteria killing. We envision that the development of advanced strategy for high efficient antibacterial hybrid nanoparticles could have broad applications in therapy and medical devices.

Hybrid polymeric therapeutic microcarriers for thermoplasmonic-triggered release of resveratrol

Diabetic retinopathy (DR) is a severe ocular complication that causes retinal damage, being one of the leading causes of blindness globally, thus the development of new strategies to prevent and treat DR as well as other degenerative diseases is highly desired. This work is focused on the design and fabrication of an ingenious model of polymeric microcapsules (MC) for controlled drug delivery in human retina cells able to carry therapeutic resveratrol (RSV) molecules in tandem with active anisotropic gold bipyramidal nanoparticles (AuBPs) as efficient photothermal agents. Specifically, MC were developed via a Layer-by-Layer deposition technique, by successively adding oppositely charged polyelectrolytes on a RSV-conjugated calcium carbonate (CaCO3) core. For the monitorization and localization of the as-formed spherical fluorescent MC inside human retina pigmented epithelial (RPE) D407 cells, fluorescein isothiocyanate, a Food and Drug Administration approved fluorophore, was attached between the polyelectrolytes layers. High-performance liquid chromatography analysis revealed a loading efficiency of over 90% of RSV on the CaCO3 core and demonstrates its release upon NIR irradiation as a consequence of the thermoplasmonic effect of MC. The cytotoxicity of the RSV-carrying MC inside human retina cells was assessed by WST-1 assay. Finally, cellular internalization and localization of the MC inside living RPE cells were monitored via Conventional Fluorescence and Re-Scanning Confocal Fluorescence Microscopy. This research seeks to take use of the novel MC and implement them as potential intraocular RSV delivery vehicles for the therapy of DR.

Highly Efficient Near-IR Photothermal Microneedles with Flame-Made Plasmonic Nanoaggregates for Reduced Intradermal Nanoparticle Deposition.

Near-infrared (NIR) photothermal therapy by microneedles (MNs) exhibits high potential against skin diseases. However, high costs, photobleaching of organic agents, low long-term stability, and potential nanotoxicity limit the clinical translation of photothermal MNs. Here, photothermal MNs are developed by utilizing Au nanoaggregates made by flame aerosol technology and incorporated in water-insoluble polymer matrix to reduce intradermal nanoparticle (NP) deposition. The individual Au interparticle distance and plasmonic coupling within the nanoaggregates are controlled by the addition of a spacer during their synthesis rendering the Au nanoaggregates highly efficient NIR photothermal agents. In situ aerosol deposition of Au nanoaggregates on MN molds results in the fabrication of photothermal MNs with thin plasmonic layers. The photothermal performance of these MN arrays is compared to ones made by three methods utilizing NP dispersions, and it is found that similar temperatures are reached with 28-fold lower Au mass due to reduced light scattering losses of the thin layers. Finally, all developed photothermal MN arrays here cause clinically relevant hyperthermia at benign laser intensities while reducing intradermal NP deposition 127-fold compared to conventional MNs made with water-soluble polymers. Such rational design of photothermal MNs requiring low laser intensities and minimal NP intradermal accumulation sets the basis for their safe clinical translation.