Tumor oxygen spatial heterogeneity is a critical challenge for the photodynamic inhibition of solid tumors. Development of an intelligent nanoagent to initiate optimal therapeutics according to the localized oxygen levels is an effective settlement. Herein, we report an activatable nanoagent (BDP-Oxide nanoparticles (NPs)) to enable the oxygen auto-adaptive photodynamic/photothermal complementary treatment. Upon the nanoagent accumulated in the tumor region, the low extracellular pH could trigger the disassociation of the nanoagent to release the phototheranostic agent, BDP-Oxide, which will subsequently afford the fluorescence imaging-guided photodynamic oxidation after it gets into the outer oxygen-rich tumors. Along with the penetration deepening in the solid tumor, furthermore, BDP-Oxide could be reduced into BDP by the cytochrome P450 (CYP450) enzymes activated in the low oxygen tension regions of inner hypoxic tumors, which will switch on the photothermal and photoacoustic effects. Overall, the BDP-Oxide NPs-enabled photodynamic/photothermal complementary therapy significantly suppressed the solid tumor growth (inhibition rate of 94.8%). This work proposes an intelligent platform to address the oxygen partial pressure for the optimization of cancer phototherapeutics.

Pulse microwave excite thermoacoustic (TA) shockwave to destroy tumor cells in situ. This has promising applications for precise tumor therapy in deep tissue. Nanoparticle (NP) with high microwave-acoustic conversion is the key to enhance the efficiency of therapy. In this study, we firstly developed defect-rich titanium nitride nanoparticles (TiN NPs) for pulse microwave excited thermoacoustic (MTA) therapy. Due to a large number of local structural defects and charge carriers, TiN NPs exhibit excellent electromagnetic absorption through the dual mechanisms of dielectric loss and resistive loss. With pulsed microwave irradiation, it efficiently converts the microwave energy into shockwave via thermocavitation effect, achieving localized mechanical damage of mitochondria in the tumor cell and yielding a precise antitumor effect. In addition to the therapeutic function, the NP-mediated TA process also generates images that provide valuable information, including tumor size, shape, and location for treatment planning and monitoring. The experimental results showed that the TiN NPs could be efficiently accumulated in the tumor via intravenous infusion. With the deep tissue penetration characteristics of microwave, the proposed TiN-mediated MTA therapy effectively and precisely cures tumors in deep tissue without any detectable side effects. The results indicated that defect-rich TiN NPs are promising candidates for tumor therapy.

Effective therapeutic strategies to precisely eradicate primary tumors with minimal side effects on normal tissue, inhibit metastases, and prevent tumor relapses, are the ultimate goals in the battle against cancer. We report a novel therapeutic strategy that combines adjuvant black phosphorus nanoparticle-based photoacoustic (PA) therapy with checkpoint-blockade immunotherapy. With the mitochondria targeting nanoparticle, PA therapy can achieve localized mechanical damage of mitochondria via PA cavitation and thus achieve precise eradication of the primary tumor. More importantly, PA therapy can generate tumor-associated antigens via the presence of the R848-containing nanoparticles as an adjuvant to promote strong antitumor immune responses. When combined with the checkpoint-blockade using anti-cytotoxic T-lymphocyte antigen-4, the generated immunological responses will further promote the infiltrating CD8 and CD4 T-cells to increase the CD8/Foxp3 T-cell ratio to inhibit the growth of distant tumors beyond the direct impact range of the PA therapy. Furthermore, the number of memory T cells detected in the spleen is increased, and these cells inhibit tumor recurrence. This proposed strategy offers precise eradication of the primary tumor and can induce long-term tumor-specific immunity.

The immense potential of carbon nanoprobes (CNPs) for using as contrast agents has propelled much recent research and development in the field of thermoacoustic (TA) molecular imaging, while the proper engineering and design of such materials with required high TA conversion efficiency is still a highly challenging task. In this work, we proposed a controllable strategy to amplify the TA conversion efficiency of the CNPs by constructing vacancy defect (VD) dipoles, and systematically demonstrated the amplification mechanism through theoretical and experimental investigations. First-principles calculation results indicate that, when a carbon atom is removed from the CNPs by chemical approach, owing to local electron density redistribution, the VDs are formed at the positions of the original carbon atoms and act as the structural origin of permanent electric dipoles with the dipole moment several orders higher than that of non-defect sites. Under pulsed microwave irradiation, the VD dipoles are polarized repeatedly and significantly contribute to the conversion efficiency from absorbed electromagnetic waves to ultrasound through enhanced dielectric relaxation losses. We experimentally synthesized graphene samples with different VD densities and VD types to demonstrate the efficiency of the proposed strategy, and results coincide well with the theoretical proposition. This work offers feasible guidance to the systematic development and rational design of new high-conversion-efficiency TA CNPs via VD engineering.

Controllably and efficaciously localized CRISPR/Cas9 plasmids transfection plays an essential role in genetic editing associated with various key human diseases. We employed near-infrared (NIR) light-responsive CRISPR/Cas9 plasmids delivery via a charge-reversal nanovector to achieve highly efficient and site-specific gene editing. The nanovector with abundant positive charges was fabricated on the basis of an ultraviolet-sensitive conjugated polyelectrolyte coated on an upconversion nanomaterial (UCNP-UVP-P), which can convert into negative charges upon 980 nm light irradiation. Using the as-prepared nanovector, we demonstrated the plasmids could be efficiently transfected into tumor cells (~ 63% ± 4%) in a time-controlled manner, and that functional CRISPR/Cas9 proteins could be successfully expressed in a selected NIR-irradiated region. Particularly, this strategy was successfully applied to the delivery of CRISPR/Cas9 gene to tumor cells in vivo, inducing high efficiency editing of the target gene PLK-1 under photoirradiation. Therefore, this precisely controlled gene regulation strategy has the potential to serve as a new paradigm for gene engineering in complex biological systems.

As a new type of cancer treatment, photoacoustic (PA) therapy is based on PA shockwave for rapid, selective and effective killing of cancer cells. The nucleus has been widely used as a target for tumor therapy, which has obtained a very considerable therapeutic effect. In situ destruction of tumor cell nucleus by photoacoustic therapy has not been studied. In this paper, a highly efficient nucleus-targeted photoacoustic theranostic polymer was developed for fluorescence and photoacoustic dual-mode imaging-guided PA therapy. The prepared polymer consists of nucleus targeting TAT peptide (TAT: YGRKKRRQRRR), hydrophilic chain poly (N,N-dimethylacrylamide) (PDMA), and near-infrared (NIR) light absorbing agent (hCyR), which can self-assemble to form nanoparticles of approximately 28 nm (denoted as TAT-PDMA-hCyR NPs). The designed nanoparticles show excellent nucleus targeting and tumor cell death (up to 80%) caused by DNA damage under pulsed laser irradiation compared to non-nucleus target counterpart PDMA-hCyR NPs without TAT peptide in vitro. As expected, the fluorescence and PA dual-mode imaging observed that TAT-PDMA-hCyR NPs were able to passively target and enrich in tumors, providing an experimental basis for in vivo treatment and thus ensuring a significant tumor inhibition rate (about 92%). In conclusion, this study provides a new and practicable method for the development of nucleus-targeting nanoparticles as potential theranostic agent for in vivo cancer imaging and therapy.

Cellular redox status presents broad implications with diverse physiological and pathological processes. Simultaneous detection of both the oxidative and reductive species of redox couples, especially the most representative pair glutathione/hydrogen peroxide (GSH/H₂O₂), is crucial to accurately map the cellular redox status. However, it still remains challenging to synchronously detect GSH/H₂O₂ in vivo due to lack of a reliable measuring tool. Herein, a ratiometric nanoprobe (UCNP-TB) possessing simultaneous delectability of GSH/H₂O₂ is established based on a multi-spectral upconverting nanophosphor (UCNP-OA) as the luminescence resonance energy transfer (LRET) donor and two dye molecules as the acceptors, including a GSH-sensitive dye (TCG) and a H₂O₂-sensitive dye (BCH). With the as-prepared UCNP-TB, real-time and synchronous monitoring the variation of GSH and H₂O₂ in vitro and in living mice can be achieved using the ratio of the upconversion luminescence (UCL) at 540 and 650 nm to that at 800 nm as the detection signal, respectively, providing highly inherent reliability of the sensing results by self-calibration. Moreover, the nanoprobe is capable of mapping the redox status within the drug-resistant tumor and the drug-induced hepatotoxic liver via ratiometric UCL imaging. Thus, this nanoprobe would provide a reliable tool to elucidate the redox state in vivo.

The probe-assisted integration of imaging and therapy into a single modality offers significant advantages in bio-applications. As a newly developed photoacoustic (PA) mechanism, plasmon-mediated nanocavitation, whereby photons are effectively converted into PA shockwaves, has excellent advantages for image-guided therapy. In this study, by simulating the laser absorption, temperature field, and nanobubble dynamics using both finite-element analysis and computational fluid dynamics, we quantified the cavitation-induced PA conversion efficiency of a water-immersed gold nanosphere, revealing new insights. Interestingly, sequential multi-bubble emission accompanied by high PA signal production occur under a single high-dose pulse of laser irradiation, enabling a cavitation-induced PA conversion efficiency up to 2%, which is ~50 times higher than that due to thermal expansion. The cavitation-induced PA signal has unique frequency characteristics, which may be useful for a new approach for in vivo nanoparticle tracking. Our work offers theoretical guidance for accurate diagnosis and controllable therapy based on plasmon-mediated nanocavitation.

Efficient probes/contrast agents are highly desirable for good-performance photoacoustic (PA) imaging, where the PA signal amplitude of a probe is dominated by both its optical absorption and the conversion efficiency from absorbed laser energy to acoustic waves. Nanoprobes have a unique micromechanism of PA energy conversion due to the size effect, which, however, has not been quantitatively demonstrated and effectively utilized. Here, we present quantitative simulations of the PA signal production process for plasmonmediated nanoprobes based on the finite element analysis method, which were performed to provide a deep understanding of their PA conversion micromechanism. Moreover, we propose a method to amplify the PA conversion efficiency of nanoprobes through the use of thermally confined shell coating, which allows the active control of the conversion efficiency beyond that of conventional probes. Additionally, we deduced the dependence of the conversion efficiency on the shell properties. Gold-nanoparticles/polydimethylsiloxane nanocomposites were experimentally synthesized in the form of gel and microfilms to verify our idea and the simulation results agreed with the experiments. Our work paves the way for the rational design and optimization of nanoprobes with improved conversion efficiency.