Bifunctional self-assembled nanoparticles with a platinated fluorophore core with ultra-low radiative transition are developed, which can generate both singlet oxygen and the photothermal effect for synergistic photodynamic and photothermal therapy with tumor ablation.
Despite numerous advanced imaging and sterilization techniques available nowadays, the sensitive in vivo diagnosis and complete elimination of drug-resistant bacterial infections remain big challenges. Here we report a strategy to design activatable theranostic nanoprobes against methicillin-resistant Staphylococcus aureus (MRSA) infections. This probe is based on silica nanoparticles coated with vancomycin-modified polyelectrolyte-cypate complexes (SiO-Cy-Van), which is activated by an interesting phenomenon of bacteria-responsive dissociation of the polyelectrolyte from silica nanoparticles. Due to the aggregation of hydrophobic cypate fluorophores on silica nanoparticles to induce ground-state quenching, the SiO-Cy-Van nanoprobes are nonfluorescent in aqueous environments. We demonstrate that MRSA can effectively pull out the vancomycin-modified polyelectrolyte-cypate complexes from silica nanoparticles and draw them onto their own surface, changing the state of cypate from off (aggregation) to on (disaggregation) and leading to in vitro MRSA-activated near-infrared fluorescence (NIRF) and photothermal elimination involving bacterial cell wall and membrane disruption. In vivo experiments show that this de novo-designed nanoprobe can selectively enable rapid (4 h postinjection) NIRF imaging with high sensitivity (10 colony-forming units) and efficient photothermal therapy (PTT) of MRSA infections in mice. Remarkably, the SiO-Cy-Van nanoprobes can also afford a long-term tracking (16 days) of the development of MRSA infections, allowing real-time estimation of bacterial load in infected tissues and further providing a possible way to monitor the efficacy of antimicrobial treatment. The strategy of bacteria-activated polyelectrolyte dissociation from nanoparticles proposed in this work could also be used as a general method for the design and fabrication of bacteria-responsive functional nanomaterials that offer possibilities to combat drug-resistant bacterial infections.
High-performance photosensitizers are highly desired for achieving selective tumor photoablation in the field of precise cancer therapy. However, photosensitizers frequently suffer from limited tumor suppression or unavoidable tumor regrowth due to the presence of residual tumor cells surviving in phototherapy. A major challenge still remains in exploring an efficient approach to promote dramatic photoconversions of photosensitizers for maximizing the anticancer efficiency. Here, a rational design of boron dipyrromethene (BDP)-based conjugated photosensitizers (CPs) that can induce dually cooperative phototherapy upon light exposure is demonstrated. The conjugated coupling of BDP monomers into dimeric BDP (di-BDP) or trimeric BDP (tri-BDP) induces photoconversions from fluorescence to singlet-to-triplet or nonradiative transitions, together with distinctly redshifted absorption into the near-infrared region. In particular, tri-BDP within nanoparticles shows preferable conversions into both primary thermal effect and minor singlet oxygen upon near-infrared light exposure, dramatically achieving tumor photoablation without any regrowth through their cooperative anticancer efficiency caused by their dominant late apoptosis and moderate early apoptosis. This rational design of CPs can serve as a valuable paradigm for cooperative cancer phototherapy in precision medicine.
Triple‐negative breast cancer (TNBC) remains with highest incidence and mortality rates among females, and a critical bottleneck lies in rationally establishing potent therapeutics against TNBC. Here, the self‐assembled micellar nanoarchitecture of heavy‐atom‐modulated supramolecules with efficient cytoplasmic translocation and tunable photoconversion is shown, for potent suppression against primary, metastatic, and recurrent TNBC. Multi‐iodinated boron dipyrromethene micelles yield tunable photoconversion into singlet oxygen and a thermal effect, together with deep penetration and subsequent cytoplasmic translocation at the tumor. Tetra‐iodinated boron dipyrromethene micelles (4‐IBMs) particularly show a distinctly enhanced cooperativity of antitumor efficiency through considerable expressions of apoptotic proteins, potently suppressing subcutaneous, and orthotopic TNBC models, together with reduced oxygen dependence. Furthermore, 4‐IBMs yield preferable anti‐metastatic and anti‐recurrent efficacies through the inhibition of metastasis‐relevant proteins, distinct immunogenic cell death, and re‐education of M2 macrophages into tumoricidal M1 phenotype as compared to chemotherapy and surgical resection. These results offer insights into the cooperativity of supramolecular nanoarchitectures for potent phototherapy against TNBC.
Accurate tumor margin demarcation in situ remains a paramount challenge. Herein, a NanoFlare (also known as spherical‐nucleic‐acid technology) based strategy is reported for in situ tumor margin delineation by transforming and amplifying the pathophysiological redox signals of tumor microenvironment. The NanoFlare designed (named AuNS‐ASON) is based on gold nanostar (AuNS) coated with a dense shell of disulfide bridge‐inserted and cyanine dyes‐labeled antisense oligonucleotides (ASON) targeting survivin mRNA. The unique anisotropic ASON‐spike nanostructure endows the AuNS‐ASON with universal cellular internalization of tumor cells, while the disulfide bridge inserted confers response specificity toward redox activation. In vitro experiments demonstrate that the AuNS‐ASON can discriminate tumor cells rapidly with activated fluorescence signals (>100‐fold) in 2 h, and further achieve synergistic gene/photothermal tumor cells ablation upon near‐infrared laser irradiation. Remarkably, in situ tumor margin delineation with high accuracy and outstanding spatial resolution (<100 µm) in mice bearing different tumors is obtained based on the AuNS‐ASON, providing intraoperative guidance for tumor resection. Moreover, the AuNS‐ASON can enable efficient neoadjuvant gene/photothermal therapy before surgery to reduce tumor extent and increase resectability. The concept of NanoFlare‐based microenvironment signal transformation and amplification could be used as a general strategy to guide the design of activatable nanoprobes for cancer theranostics.
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