Photodynamic therapy (PDT) efficacy is limited by the random intracellular distribution of conventional photosensitizers (PSs), as reactive oxygen species (ROS) have an extremely short half-life. Organelle-targeted PSs can enhance PDT efficacy by concentrating ROS at critical subcellular sites, yet systematic evaluation and comparison of different organelle targets using a uniform parent PS remain scarce. Herein, a panel of organelle-targeted PSs using pyropheophorbide a (Ppa) as the parent photosensitizer was synthesized via a facile amide condensation reaction, including mitochondria-targeted PS (Ppa-Mit), lysosome-targeted PS (Ppa-Lys), endoplasmic reticulum-targeted PS (Ppa-ER), and nucleus-targeted PS (Ppa-Nuc). These PSs retained the optical properties of parent Ppa and exhibited precise organelle localization. Ppa-Mit showed the highest cellular uptake and ROS generation, while Ppa-Lys displayed the strongest photocytotoxicity with the lowest IC50 (0.109 μM) against Panc02 cells. Flow cytometry confirmed that all PSs induced tumor cell death primarily via inducing cell apoptosis. Notably, in this study, lysosome-targeted Ppa (Ppa-Lys) exhibited the strongest photocytotoxicity among the four organelle-targeted PSs tested in Panc02 cells. This study demonstrates lysosomal-targeting modification of PSs as a universal and effective strategy to improve the antitumor efficacy of PDT, providing valuable insights for rational PS design.

Sonodynamic therapy (SDT) is a promising non-invasive modality for cancer treatment, leveraging ultrasound to activate therapeutic agents deep within tissues. However, its clinical translation has been hampered by inefficient reactive oxygen species (ROS) generation, limited tumor-specific accumulation, and poor penetration across biological barriers such as the blood-tumor barrier (BTB). To address these challenges, we engineered ultrasmall core-shell nanosonosensitizers composed of porphyrin-grafted lipids (PGL) encapsulating gold nanoparticles (AuNPs), and further functionalized them with the tumor-homing peptide CREKA (Cys-Arg-GluLys-Ala), forming Au@PGL-CREKA (APC) nanoparticles. The sub-10 nm size of APC facilitates effective traversal of physiological barriers and deep tumor penetration. The gold core synergistically enhances the sonodynamic activity of porphyrins, significantly boosting ROS production under ultrasound irradiation. Targeting via CREKA improves selective tumor accumulation while reducing hepatic uptake, thereby increasing extrahepatic delivery. In a U87 solid tumor mouse model, APC SDT treatment with low-intensity focused ultrasound (LIFU) led to pronounced tumor regression and minimal off-target toxicity. These findings underscore the potential of APC as a targeted, deep-penetrating, and highly efficient sonosensitizer platform for treating aggressive solid tumors such as glioblastoma (GBM).

ABSTRACT The precise intraoperative delineation of gastric tumors and their micrometastases remains a major challenge in surgical oncology. To address this, we developed a novel NIR‐II fluorescent probe named SPN01 targeting integrin αvβ3, a receptor upregulated in gastric cancer and associated tumor vasculature. SPN01 was constructed by conjugating RGD peptide to a high‐performance cyanine fluorophore with net neutral charge. In multiple preclinical models, SPN01 enabled high‐contrast visualization of sub‐centimeter orthotopic tumors, detection of occult peritoneal micrometastases as small as 0.5 mm, and specific identification of metastatic lymph nodes. Concurrently, near‐infrared II (NIR‐II, 900–1880 nm) fluorescence guidance facilitated the complete resection of tumors with clear margins, owing to the superior brightness of SPN01 in the NIR‐II window. Notably, ex vivo validation using human gastric cancer specimens confirmed target‐specific binding. Comprehensive pharmacokinetic and safety studies demonstrated rapid dual‐pathway clearance and no obvious toxicity. Following these findings, we conducted a first‐in‐human Phase I clinical trial involving 24 healthy volunteers, which demonstrated a favorable safety profile for SPN01. These findings support SPN01‐assisted NIR‐II fluorescence‐guided surgery as a promising candidate for clinical translation with the potential to enhance the completeness of gastric cancer resection.

Background Microcirculatory disturbances emerging during ischemia–reperfusion critically influence tissue perfusion in acute ischemic stroke. However, existing imaging approaches are limited in their ability to continuously capture brain-wide cerebrovascular dynamics across spatial scales, restricting observation of rapid vascular and microcirculatory changes during the ischemia–reperfusion process. Methods We developed a 2.10-g dual-plane wearable ultrasound imaging platform that enables stable, long-duration monitoring of cerebrovascular dynamics throughout the entire ischemia–reperfusion process in mice. Functional ultrasound imaging was used to assess vascular function and cerebral blood volume dynamics, while ultrasound localization microscopy provided micrometer-resolution mapping of the microvascular architecture. Spatiotemporal analyses were performed to characterize hemodynamic wave propagation, vascular structural deformation, and regional differences in reperfusion dynamics. Results Simultaneous assessment of cerebral blood volume and microvascular architecture revealed multiple dimensions of cerebrovascular dynamics during ischemia–reperfusion, including recurrent spreading depolarization–associated hemodynamic waves, progressive vascular deformation and heterogeneous patterns of microvascular reperfusion. Continuous ULM imaging further enabled longitudinal tracking of perfused vascular pathways, highlighting dynamic changes in the spatial organization of microvascular networks over time. Conclusions This wearable dual-plane ultrasound platform enables long-duration monitoring of brain-wide cerebrovascular dynamics while providing super-resolution characterization of the microvascular network. The approach offers a methodological framework for investigating the temporal evolution of cerebrovascular organization during acute ischemia–reperfusion.

ABSTRACT Photodynamic therapy (PDT) is a promising cancer treatment with minimal invasiveness and high selectivity, but its efficacy depends heavily on subcellular reactive oxygen species (ROS) localization. Although organelle‐targeted PDT can enhance antitumor effects, systematic evaluation and comparison of their photocytotoxicity, and photoimmunological activation capacity remain lacking. Herein, we synthesized four organelle‐targeted photosensitizers (PSs) using pyropheophorbide a (Ppa) as the core scaffold: Ppa‐Mit, Ppa‐Lys, Ppa‐ER, and Ppa‐Nuc, which target mitochondria, lysosomes, endoplasmic reticulum (ER), and nucleus, respectively. These PSs were then individually encapsulated into synthetic high‐density lipoprotein (sHDL) nanodiscs to yield PMN, PLN, PEN, and PNN. All nanodiscs achieved specific organelle targeting. Photocytotoxicity followed the order PLN > PMN > PNN > PEN, while PMN exhibited the optimal immunogenic cell death (ICD)‐inducing capacity by triggering robust secretion of damage‐associated molecular patterns (DAMPs). In vivo, PMN and PLN achieved complete, recurrence‐free tumor ablation, promoting infiltration of mature dendritic cells, and cytotoxic CD8+ T cells (expressing Granzyme B) to elicit strong antitumor immunity. This study identifies PMN and PLN as promising PDT agents and highlights mitochondria‐targeted and lysosome‐targeted PDT as a favorable approach for effective tumor photoimmunotherapy, providing guidance for the rational design of targeted PSs.

Significance Glioblastoma, has poor prognosis. Sonodynamic therapy (SDT) offers a new non-invasive treatment approach. Approach This clinical trial assesses SDT combined with radiotherapy and chemotherapy. Results Among 19 patients, 68.4% showed stable disease and 15.8% achieved partial remission at six months. Median progression-free survival was 7.6 months, and overall survival was 9.47 months. Conclusions SDT combined with radiotherapy and chemotherapy shows promise in treating glioblastoma, improving survival and symptoms.

Plane wave imaging (PWI) is pivotal in medical ultrasound (US), prized for its ultrafast capabilities essential for real-time physiological monitoring. Traditionally, enhancing image quality in PWI has necessitated an increase in the number of plane waves (PWs), unfortunately compromising its hallmark high frame rates. To fully leverage the frame rate advantage of PWI, existing deep-learning-based methods often use single-PW as the sole input for training strategies to replicate multi-PWs compounding results. However, these typically fail to capture the intricate information provided by steered waves. In response, we have developed a sophisticated architecture that implicitly integrates multiangle information by generating and dynamically combining virtual steered PWs within the network. Using deep learning (DL) techniques, this system creates virtual steered waves from the single primary input view, simulating a limited number of steering angles. These virtual PWs are then expertly merged with actual single-PW data through an advanced attention mechanism. Through implicit multiangle acoustic synthesis, our approach achieves the high-quality output typically associated with extensive multiangle compounding. Rigorously evaluated on datasets acquired from simulations, experimental phantoms, and in vivo targets, our method has demonstrated superior performance over traditional single-PW strategies by providing more stable, reliable, and robust imaging outcomes. It excels in restoring detailed speckle patterns and diagnostic characteristics crucial for in vivo imaging, thereby offering a promising advancement in PWI technology without sacrificing speed. The code of the network is publicly available at https://github.com/yijiaLiu12/Implicit-Plane-Wave-Synthesis.

Antimicrobial peptides (AMPs) are a unique class of bioactive compounds with applications in antimicrobial therapy, anti-inflammatory regulation, and drug delivery. As antibiotic resistance escalates globally, AMPs have emerged as one of the most promising alternatives to conventional antibiotics. Nevertheless, their clinical utility is limited by pH-dependent instability and enzymatic degradation in vivo. Hydrogels, as versatile polymers, offer solutions through their tunable biological properties. Recent advances at the material-biomedical interface have spurred innovative strategies to engineer AMP hydrogels, overcoming intrinsic limitations. This review presents a comprehensive analysis and discussion of various synthetic approaches to antimicrobial peptide hydrogels, with particular emphasis on mechanisms involving the modulation of reactive oxygen species. Additionally, the current state of antimicrobial peptide hydrogels is explored within antifungal therapy, wound healing, cancer treatment, bioimaging, nucleic acid delivery, immunomodulation, and surgical implants. Finally, we offer a concise perspective on the future trajectory of antimicrobial peptide hydrogel research. We aim to provide a theoretical framework for ongoing studies in this domain and inspire innovative avenues for future investigations.

Liver cancer remains a significant global health challenge, with rising incidence rates and limited treatment options, underscoring the urgent need for innovative and effective therapeutic strategies. Sonodynamic therapy (SDT) stands as a promising non-invasive treatment technique, yet its advancement faces challenges due to difficulties in precisely co-localizing the tumor, sonosensitizers, and focused ultrasound (FUS). Additionally, the absence of feasible methods for in vivo detection of reactive oxygen species (ROS) hampers further research and development in this field. Herein, our study introduces a novel sonosensitizer, a phthalocyanine-conjugated mesoporous silicate nanoparticle loaded with allylhydrazine (PAMSN). We confirm that PAMSN not only amplifies the fluorescent signal of phthalocyanine (1.9-fold) but also generates nitrogen gas bubbles via the interaction between allylhydrazine (ALZ) and ROS. This distinct attribute positions PAMSN as a versatile multimodal contrast agent suitable for in vivo tumor imaging and SDT applications. Moreover, we establish a FUS platform that integrates fluorescent and ultrasonic imaging guidance, ensuring the precise delivery of ultrasound to the targeted area. In conjunction with PAMSN, this platform can effectively treat orthotopic liver cancer in a murine model while in vivo monitoring of ROS and detection of cavitation are enabled. In conclusion, PAMSN-mediated SDT with the multimodal imaging-guided SDT platform facilitates a precise and controllable SDT process, providing a promising tool for safer and more effective SDT in clinical tumor treatment.

Signif. Brainstem gliomas lack effective treatments. SDT is a new non-invasive option. Approach Trial assesses SDT + RT + CT for high-grade brainstem gliomas. Results 3/11 patients had partial response. Median PFS 9.2 mos, OS 11.7 mos. 6-mo PFS 54.5%, OS 72.7%. Concls. SDT + chemo-radiotherapy is safe, feasible, with initial therapeutic promise.

Photodynamic therapy (PDT) has received increasing attention because it can induce immunogenic cell death (ICD) and activate the STING pathway. However, the immune response induced by PDT is limited by its poor DNA damage, due to random intracellular distribution of the photosensitizer and the repair mechanism of cells. To this end, a liposomal nanophotosensitizer PNOR, modified with arginylglycylaspartic acid (RGD) peptide on the surface and coloaded with nucleus-targeting photosensitizer Ppa-Nuc and DNA repair inhibitor Olaparib (Ola), is developed to improve photoimmunotherapy. PNOR reveals exceptional nucleus-targeting capability, and nucleus-targeted PDT is demonstrated to induce substantial ICD and robust STING pathway activation in vitro. PNOR effectively enhances dendritic cell maturation and activation of cytotoxic T cells, thus exhibiting remarkable antitumor efficacy in both primary and distant tumors in a bilateral subcutaneous pancreatic tumor model. PNOR represents a promising strategy for improving photoimmunotherapy by inducing efficient DNA oxidative damage to simultaneously activate an innate and adaptive immune response.

Proteolysis-targeting chimeras (PROTACs) have emerged as a breakthrough therapeutic strategy in oncology, enabling the selective degradation of traditionally "undruggable" proteins via the ubiquitin-proteasome system. However, their clinical translation remains challenging due to high molecular weight, limited aqueous solubility, and metabolic instability, which limit systemic bioavailability and tumor penetration. To address these challenges, a variety of nanocarrier systems have been developed to improve the stability, pharmacokinetics, and tumor-specific accumulation of PROTACs. Beyond delivery enhancement, nanotechnology also enables the creation of next-generation PROTAC modalities, such as mRNA-encoded and RNA-scaffolded PROTACs, thereby expanding their therapeutic potential. In parallel, stimuli-responsive nanocarriers offer spatiotemporal control over PROTAC release, maximizing therapeutic efficacy while minimizing off-target effects. This review provides a comprehensive overview of nanotechnology-enabled strategies for PROTAC delivery, highlights key translational challenges, and discusses future directions to facilitate their clinical advancement in cancer therapy.

ABSTRACT Tumor drug resistance has been reported to be associated with drug efflux in tumor cells. Recently, a noninvasive and safe mechanism, sonodynamic therapy (SDT), has been proposed to be an oxidative stress strategy to potentially overcome drug efflux, but with efficacy limitation. Herein, we propose a systematic strategy for optimizing SDT, especially revealing the key role of acoustics parameters acting in SDT efficiency. A doxorubicin (DOX)‐loaded sonosensitive micelle (DPM) mediated “sono‐force” combination (chemotherapy and sonodynamic) therapy strategy, named DPCSTs, which was designed for amplifying SDT to augment oxidative stress to overcome drug efflux and induce robust long‐term inhibition of tumor development by optimized acoustic parameters. The sub‐10 nm size DPM enhanced tumor targeting and renal clearance. Meanwhile, another important component, doxorubicin, significantly suppressed residual tumors (78.6%) due to “sono‐force” augmented oxidative stress reversing drug efflux, finally leading to long‐term tumor development limitation in vivo. It is the first time to propose a systematic strategy for optimizing SDT regimens to overcome resistance, which can synergize with chemotherapy to exert long‐term tumor development inhibition. We believe that this work will advance SDT‐related research to a new level, and improve our understanding of overcoming resistance of targeted cancer therapy.

The treatment selection for recurrent hepatocellular carcinoma (rHCC) within Milan criteria after hepatectomy remains challenging. Here, we present HEROVision, a Vision Transformer-based model designed for personalized prognosis prediction and treatment optimization between thermal ablation (TA) and surgical resection (SR). HEROVision is trained on initial HCC cohorts (8492 images; 772 patients) and independently tested on rHCC cohorts (9163 images; 833 patients) from five centers. Propensity score matching (PSM) forms two groups of rHCC patients underwent TA and SR to fairly evaluate whether optimized treatment selection by HEROVision have clinical benefits. HEROVision significantly outperforms all six guideline staging systems in the external testing cohort, both in time-dependent concordance index and area under the curve (all P < 0.002). After PSM, 35.9% (23/64) and 6.6% (6/91) high-risk rHCC patients are identified, who could achieve improved prognosis by changing their treatments. HEROVision shows promise in optimizing individualized treatment between TA and SR for early-stage rHCC, complementing current clinical guidelines.

Cryogels are a class of macroporous hydrogels fabricated through a cryogelation process at sub-zero temperatures, resulting in a highly interconnected pore structure. This review focuses on cryogels that mimic the natural extracellular matrix (ECM) in composition and molecular architecture. These cryogels not only exhibit the high mechanical strength and elasticity characteristic of traditional cryogels but also possess unique structural features and excellent biocompatibility, providing a supportive microenvironment for cellular vitality and metabolic activity. The interconnected pores of cryogels facilitate the establishment of controllable mass transport and oxygen gradients, making them particularly advantageous for applications such as hypoxic tumor modeling where precise microenvironment control is essential. They also show great promise in vaccine development, drug delivery and screening, and combination chemotherapies. These features position cryogels as an ideal platform for cancer research. This review summarizes the principles, processes, and preparation methods of cryogelation for developing ECM-mimicking cryogels. Furthermore, it discusses the effects of polymer composition, crosslinking agents, freezing conditions, and other factors on the physical, chemical, and biological properties of cryogels. Finally, the biomedical applications of ECM-mimicking cryogels are explored, illustrating their potential roles in tissue engineering, cancer research, and therapeutic interventions.

Hepatocellular carcinoma (HCC) is the most common primary malignant disease of the liver. Although immunotherapy offers new opportunities for treating advanced HCC, its therapeutic effect is still limited by the immunosuppressive tumor microenvironment (TME). Herein, a nanosensitizer RGD@Ce6@MSA-2@Liposome (RCM-Lip) is synthesized to specifically initiate the HCC tumor immune microenvironment through sonodynamic therapy (SDT)-triggered immunogenic cell death (ICD) and MSA-2-activated cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. RCM-Lip consists of a sonosensitizer (Chlorin e6, Ce6) with a STING agonist (MSA-2) and a tumor targeting peptide RGD inserted on the outer liposome surface. Under ultrasound irradiation, RCM-Lip generates reactive oxygen species that induce cytotoxicity and apoptosis of tumor cells. Meanwhile, tumor antigens released by apoptosis are taken up by dendritic cells (DCs), while STING is activated in the DCs by MSA-2. Moreover, DC maturation is stimulated, further enhancing the systematic anti-tumor immune responses. Sono-immunotherapy mediated by RCM-Lip promotes DCs maturation and tumor infiltration of CD8+T cells, increasing inflammatory cytokine secretion. Consequently, the immunologically "cold" TME of HCC is successfully turned into a "hot" one, leading to a significant tumor suppression effect with good bio-safety. These results suggest a promising method for precise tumor targeting and synergistic cancer sono-immunotherapy. STATEMENT OF SIGNIFICANCE: Our study addressed the therapeutic dilemma of hepatocellular carcinoma (HCC) as an immunological "cold" tumor by the synergistic application of sonodynamic therapy (SDT) and STING agonist. The cGAS-STING signaling pathway plays a pivotal role in innate immunity against cancer, but the clinical application of STING agonists were hampered by inflammatory responses due to off-target activation. Our innovative solution introduces RGD-targeted peptide to encapsulate sonosensitizer and STING agonist, strengthening therapeutic effects and reducing systemic toxicity. The targeted sono-immunotherapy promoted DCs maturation and tumor infiltration of CD8+T cells, producing intense tumor-killing effect on mice model with good bio-safety. As a result, the immunological "cold" tumor microenvironment of HCC is successfully turned into a "hot" one.

Plane wave imaging (PWI) enables ultrafast ultrasound acquisition but often suffers from degraded image quality due to the lack of transmit focusing. To overcome this limitation, we propose Virtual Receive Compounding (ViRC), a general framework that enhances single-plane wave imaging by synthesizing multiple virtual receive angles. By constructing virtual arrays and applying angle-dependent delays at the reception side, ViRC achieves coherent multi-angle compounding without additional transmissions. This approach improves lateral resolution and significantly enhances image contrast. Phantom and in vivo experiments show that ViRC yields 1-2 dB gains in contrast metrics for phantoms and up to 3 dB improvements in vivo, while maintaining similar noise levels. Moreover, ViRC can be seamlessly combined with advanced beamforming methods, establishing it as an efficient and versatile solution for high-quality ultrafast ultrasound imaging.

Plane wave imaging (PWI) is a cornerstone of ultrafast ultrasound imaging, but its application is often hindered by limitations in image quality due to the simultaneous transmission of unfocused plane waves. To address this challenge, we propose a novel framework, Virtual Multi-Angle Receive Compounding (VMARC), designed specifically to enhance image quality in single-plane wave imaging. By introducing virtual receive arrays and simulating multiple receive angles, VMARC enables coherent compounding of signals at the reception side, effectively improving lateral resolution, contrast ratio (CR), and contrast-to-noise ratio (CNR). Experiments on phantom and in vivo datasets demonstrate that VMARC achieves 1-2 dB improvements in CR and CNR for phantoms and approximately 3 dB in vivo, along with significant lateral resolution enhancements. The process's flexibility allows seamless integration with advanced beamforming techniques, establishing it as a general framework for optimizing single-plane wave imaging quality across a range of ultrasound applications.

Purpose: To assess the anticancer effect of microbubbles (MBs) in combination with sinoporphyrin sodium (DVDMS)-mediated sonodynamic therapy (SDT) for the in vitro and in vivo treatment of hepatocellular carcinoma (HCC). Methods: HepG2 cells were used for in vitro experiments. Reactive oxygen species (ROS) production was detected using 2',7'-dichlorodihydrofluorescein diacetate and singlet oxygen sensor green in vitro and in solution, respectively. Cytotoxicity was evaluated using a Cell Counting Kit 8 assay and the calcein AM/PI double-staining method. Annexin V-FITC/PI staining was employed to analyze the rate of cell apoptosis. Cell surface calreticulin exposure, high mobility group box 1 release, and adenosine triphosphate secretion were measured to detect immunogenic cell death (ICD). The anticancer effect of the combination therapy was further assessed in Hepa1-6 tumor-bearing mice. Results: Compared with SDT alone, ROS production in the MBs + SDT group was enhanced 1.2-fold (p < 0.0001). The cytotoxic effect of DVDMS-mediated SDT on HepG2 cells was concentration-dependent, and the additional application of MBs increased cytotoxicity. Additionally, MBs augmented the SDT-induced apoptosis rate from 33.26 ± 13.48 to 72.95 ± 7.95% (p < 0.01). Notably, our results demonstrated that MBs can enhance SDT-induced ICD. In in vivo experiments, SDT combined with MBs significantly reduced tumor volume, with negligible differences in mouse body weight. Furthermore, MBs effectively enhanced SDT-induced tumor tissue destruction. Conclusion: The present study indicates that MBs can markedly improve the anticancer effects of SDT in HCC.

Cancer therapy remains a critical medical challenge. Immunotherapy is an emerging approach to regulating the immune system to fight cancer and has shown therapeutic potential. Due to their immunogenicity, bacteria have been developed as drug-delivery vehicles in cancer immunotherapy. However, ensuring the safety and efficacy of this approach poses a considerable challenge. This paper comprehensively explains the fundamental processes and synthesis principles involved in immunotherapy utilizing engineered bacteria. Initially, we list common engineered strains and discuss that growth control through genetic mutation promises therapeutic safety. By considering the characteristics of the tumor microenvironment and the interaction of specific molecules, the precision targeting of tumors can be improved. Furthermore, we present a foundational paradigm for genetic circuit construction to achieve controlled gene activation and logical expression, directly determining drug synthesis and release. Finally, we review the immunogenicity, the expression of immunomodulatory factors, the delivery of immune checkpoint inhibitors, and the utilization of bacteria as tumor vaccines to stimulate the immune system and facilitate the efficacy of cancer immunotherapy.