Fueling sentinel node via reshaping cytotoxic T lymphocytes with a flex-patch for post-operative immuno-adjuvant therapy.

Clinical updates suggest conserving metastatic sentinel lymph nodes (SLNs) of breast cancer (BC) patients during surgery; however, the immunoadjuvant potential of this strategy is unknown. Here we leverage an immune-fueling flex-patch to animate metastatic SLNs with personalized antitumor immunity. The flex-patch is implanted on the postoperative wound and spatiotemporally releases immunotherapeutic anti-PD-1 antibodies (aPD-1) and adjuvants (magnesium iron-layered double hydroxide, LDH) into the SLN. Genes associated with citric acid cycle and oxidative phosphorylation are enriched in activated CD8+ T cells (CTLs) from metastatic SLNs. Delivered aPD-1 and LDH confer CTLs with upregulated glycolytic activity, promoting CTL activation and cytotoxic killing via metal cation-mediated shaping. Ultimately, CTLs in patch-driven metastatic SLNs could long-termly maintain tumor antigen-specific memory, protecting against high-incidence BC recurrence in female mice. This study indicates a clinical value of metastatic SLN in immunoadjuvant therapy.

Engineering Radiosensitizer-Based Metal-Phenolic Networks Potentiate STING Pathway Activation for Advanced Radiotherapy.

Radiotherapy, a mainstay of first-line cancer treatment, suffers from its high-dose radiation-induced systemic toxicity and radioresistance caused by the immunosuppressive tumor microenvironment. The synergy between radiosensitization and immunomodulation may overcome these obstacles for advanced radiotherapy. Here, the authors propose a radiosensitization cooperated with stimulator of interferon genes (STING) pathway activation strategy by fabricating a novel lanthanide-doped radiosensitizer-based metal-phenolic network, NaGdF4 :Nd@NaLuF4 @PEG-polyphenol/Mn (DSPM). The amphiphilic PEG-polyphenol successfully coordinates with NaGdF4 :Nd@NaLuF4 (radiosensitizer) and Mn2+ via robust metal-phenolic coordination. After cell internalization, the pH-responsive disassembly of DSPM triggers the release of their payloads, wherein radiosensitizer sensitizes cancer cells to X-ray and Mn2+ promote STING pathway activation. This radiosensitizer-based DSPM remarkably benefits dendritic cell maturation, anticancer therapeutics in primary tumors, accompanied by robust systemic immune therapeutic performance against metastatic tumors. Therefore, a powerful radiosensitization with STING pathway activation mediated immunostimulation strategy is highlighted here to optimize cancer radiotherapy.

NIR II-Excited and pH-Responsive Ultrasmall Nanoplatform for Deep Optical Tissue and Drug Delivery Penetration and Effective Cancer Chemophototherapy.

The limited tumor tissue penetration of many nanoparticles remains a formidable challenge to their therapeutic efficacy. Although several photonanomedicines have been applied to improve tumor penetration, the first near-infrared window mediated by the low optical tissue penetration depth severely limits their anticancer effectiveness. To achieve deep optical tissue and drug delivery penetration, a near-infrared second window (NIR-II)-excited and pH-responsive ultrasmall drug delivery nanoplatform was fabricated based on BSA-stabilized CuS nanoparticles (BSA@CuS NPs). The BSA@CuS NPs effectively encapsulated doxorubicin (DOX) via strong electrostatic interactions to form multifunctional nanoparticles (BSA@CuS@DOX NPs). The BSA@CuS@DOX NPs had an ultrasmall size, which allowed them to achieve deeper tumor penetration. They also displayed stronger NIR II absorbance-mediated deep optical tissue penetration than that of the NIR I window. Moreover, the multifunctional nanoplatform preferentially accumulated in tumor sites, induced tumor hyperthermia, and generated remarkably high ROS levels in tumor sites upon NIR-II laser (1064 nm) irradiation. More importantly, our strategy achieved excellent synergistic effects of chemotherapy and phototherapy (chemophototherapy) under the guidance of photothermal imaging. The developed nanoparticles also showed good biocompatibility and bioclearance properties. Therefore, our work demonstrated a facile strategy for fabricating a multifunctional nanoplatform that is a promising candidate for deep tumor penetration as an effective antitumor therapy.

Photoacoustic Imaging-Trackable Magnetic Microswimmers for Pathogenic Bacterial Infection Treatment.

Micro/nanorobots have been extensively explored as a tetherless small-scale robotic biodevice to perform minimally invasive interventions in hard-to-reach regions. Despite the emergence of versatile micro/nanorobots in recent years, matched in vivo development remains challenging, limited by unsatisfactory integration of core functions. Herein, we report a polydopamine (PDA)-coated magnetic microswimmer consisting of a magnetized Spirulina (MSP) matrix and PDA surface. Apart from the properties of the existing MSP (e.g., robust propulsion, natural fluorescence, tailored biodegradation, and selective cytotoxicity), the introduced PDA coating enhances the photoacoustic (PA) signal and photothermal effect of the MSP, thus making PA image tracking and photothermal therapy possible. Meanwhile, the PDA's innate fluorescence quenching and diverse surface reactivity allows an off-on fluorescence diagnosis with fluorescence probes (e.g., coumarin 7). As a proof of concept, real-time image tracking (by PA imaging) and desired theranostic capabilities of PDA-MSP microswimmer swarms are demonstrated for the treatment of pathogenic bacterial infection. Our study suggests a feasible antibacterial microrobot for in vivo development and a facile yet versatile functionalization strategy of micro/nanorobots.

Functional long circulating single walled carbon nanotubes for fluorescent/photoacoustic imaging-guided enhanced phototherapy.

Nanotherapeutics have been investigated for years, but only modest survival benefits were observed clinic. This is partially attributed to the short and rapid elimination of nanodrug after intravenous administration. In this study, a long circulation single wall carbon nanotube (SWCNT) complex was successfully fabricated through a new SWCNT dispersion agent, evans blue (EB). The complex was endowed with fluorescent imaging and photodynamic therapy ability by self-assembly loading an albumin coupled fluorescent photosensitizer, Chlorin e6 (Ce6) via the high affinity between EB and albumin. The yielding multifunctional albumin/Ce6 loaded EB/carbon nanotube-based delivery system, named ACEC, is capable of providing fluorescent and photoacoustic imaging of tumors for optimizing therapeutic time window. Synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) were carried out as guided by imaging results at 24 h post-injection and achieved an efficient tumor ablation effect. Compared to PDT or PTT alone, the combined phototherapy managed to damage tumor and diminish tumor without recurrence. Overall, our study presents a SWCNT based theranostic system with great promising in dual modalities imaging guided PTT/PDT combined treatment of tumor. The applications of EB on SWCNT functionalization can be easily extended to the other nanomaterials for improving their in vivo stability and circulation time.