Surface-engineered erythrocyte membrane-camouflage fluorescent bioprobe for precision ovarian cancer surgery.

PURPOSE: Fluorescence imaging-guided surgery has been used in oncology. However, for tiny tumors, the current imaging probes are still difficult to achieve high-contrast imaging, leading to incomplete resection. In this study, we achieved precise surgical resection of tiny metastatic cancers by constructing an engineering erythrocyte membrane-camouflaged bioprobe (AR-M@HMSN@P). METHODS: AR-M@HMSN@P combined the properties of aggregation-induced emission luminogens (AIEgens) named PF3-PPh3 (P), with functional erythrocyte membrane modified by a modular peptide (AR). Interestingly, AR was composed of an asymmetric tripodal pentapeptide scaffold (GGKGG) with three appended modulars: KPSSPPEE (A6) peptide, RRRR (R4) peptide and cholesterol. To verify the specificity of the probe in vitro, SKOV3 cells with overexpression of CD44 were used as the positive group, and HLF cells with low expression of CD44 were devoted as the control group. The AR-M@HMSN@P fluorescence imaging was utilized to provide surgical guidance for the removal of micro-metastatic lesions. RESULTS: In vivo, the clearance of AR-M@HMSN@P by the immune system was reduced due to the natural properties inherited from erythrocytes. Meanwhile, the A6 peptide on AR-M@HMSN@P was able to specifically target CD44 on ovarian cancer cells, and the electrostatic attraction between the R4 peptide and the cell membrane enhanced the firmness of this targeting. Benefiting from these multiple effects, AR-M@HMSN@P achieved ultra-precise tumor imaging with a signal-to-noise ratio (SNR) of 15.2, making it possible to surgical resection of tumors < 1 mm by imaging guidance. CONCLUSION: We have successfully designed an engineered fluorescent imaging bioprobe (AR-M@HMSN@P), which can target CD44-overexpressing ovarian cancers for precise imaging and guide the resection of minor tumors. Notably, this work holds significant promise for developing biomimetic probes for clinical imaging-guided precision cancer surgery by exploiting their externally specified functional modifications.

Effective Therapy of Drug-Resistant Bacterial Infection by Killing Planktonic Bacteria and Destructing Biofilms with Cationic Photosensitizer Based on Phosphindole Oxide.

Developing effective therapies to fight against biofilm-associated infection is extremely urgent. The complex environment of biofilm forces the bacteria to evade the elimination of antibiotics, resulting in recalcitrant chronic infections. To address this issue, a cationic antibacterial agent based on phosphindole oxide (ß-PM-PIO) is designed and prepared. The unique molecular structure endows ß-PM-PIO with aggregation-induced emission feature and efficient singlet oxygen generation ability. ß-PM-PIO shows excellent visual diagnostic function to planktonic bacteria and biofilm. In addition, owing to the synergistic effect of phototoxicity and dark toxicity, ß-PM-PIO can achieve superb antibacterial and antibiofilm performance against Gram-positive bacteria with less potential of developing drug resistance. Notably, ß-PM-PIO also holds excellent anti-infection capacity against drug-resistant bacteria in vivo with negligible side effects. This work offers a promising platform to develop advanced antibacterial agents against multidrug-resistant bacterial infection.

Aggregation-induced emission photosensitizer-based photodynamic therapy in cancer: from chemical to clinical.

Cancer remains a serious threat to human health owing to the lack of effective treatments. Photodynamic therapy (PDT) has emerged as a promising non-invasive cancer treatment that consists of three main elements: photosensitizers (PSs), light and oxygen. However, some traditional PSs are prone to aggregation-caused quenching (ACQ), leading to reduced reactive oxygen species (ROS) generation capacity. Aggregation-induced emission (AIE)-PSs, due to their distorted structure, suppress the strong molecular interactions, making them more photosensitive in the aggregated state instead. Activated by light, they can efficiently produce ROS and induce cell death. PS is one of the core factors of efficient PDT, so proceeding from the design and preparation of AIE-PSs, including how to manipulate the electron donor (D) and receptor (A) in the PSs configuration, introduce heavy atoms or metal complexes, design of Type I AIE-PSs, polymerization-enhanced photosensitization and nano-engineering approaches. Then, the preclinical experiments of AIE-PSs in treating different types of tumors, such as ovarian cancer, cervical cancer, lung cancer, breast cancer, and its great potential clinical applications are discussed. In addition, some perspectives on the further development of AIE-PSs are presented. This review hopes to stimulate the interest of researchers in different fields such as chemistry, materials science, biology, and medicine, and promote the clinical translation of AIE-PSs.

Macrophage Membrane-Camouflaged Aggregation-Induced Emission Nanoparticles Enhance Photodynamic-Immunotherapy to Delay Postoperative Tumor Recurrence.

Surgery is a traditional tumor treatment, and immunotherapy can reduce the postoperative recurrence of tumors. However, the intrinsic limits of low responsive rate and non-tumor specificity of immunotherapy agents are still insufficient to address therapeutic demands. Herein, the macrophages membrane camouflaged nanoparticles (NPs), named M@PFC, consisting of the aggregation-induced emission photosensitizer (PF3-PPh3 ) and immune adjuvant (CpG), are reported. As the protein on the membrane interacts with the vascular cell adhesion molecule 1 (VCAM-1) of cancer cells, M@PFC efficiently transports CpG to the tumor. Meanwhile, M@PFC can evade clearance by the immune system and prolong the circulation time in vivo; thus, enhancing their accumulation in tumors. PF3-PPh3 promotes high production of reactive oxygen species (ROS) and triggers immune cell death (ICD) in tumor cells under light exposure. Importantly, CpG enrichment in tumors can stimulate tumor cells to produce immune factors to assist in enhancing ICD effects. The synergistic effect combining the PDT properties of the aggregation-induced emission (AIE)-active photosensitizer and immunotherapy properties of CpG significantly delays tumor recurrence after surgery. In conclusion, this strategy achieves the synergistic activation of the immune system for anti-tumor activity, providing a novel paradigm for the development of therapeutic nanodrugs to delay postoperative tumor recurrence.

Short-Wavelength Aggregation-Induced Emission Photosensitizers for Solid Tumor Therapy: Enhanced with White-Light Fiber Optic.

Background: White-light photodynamic therapy (wPDT) has been used in the treatment of cancer due to its convenience, effectiveness and less painful. However, the limited penetration of white-light into the tissues leads to a reduced effectiveness of solid tumor treatment. Methods: Two short-wavelength aggregation-induced emission (AIE) nanoparticles were prepared, PyTPA@PEG and TB@PEG, which have excitation wavelengths of 440 nm and 524 nm, respectively. They were characterized by UV, fluorescence, particle size and TEM. The ability of nanoparticles to produce reactive oxygen species (ROS) and kill cancer cells under different conditions was investigated in vitro, including white-light, after white-light penetrating the skin, laser. A white-light fiber for intra-tumor irradiation was customized. Finally, induced tumor elimination with fiber-mediated wPDT was confirmed in vivo. Results: In vitro, both PyTPA@PEG and TB@PEG are more efficient in the production ROS when exposed to white-light compared to laser. However, wPDT also has a fatal flaw in that its level of ROS production after penetrating the skin is reduced to 20-40% of the original level. To this end, we have customized a white-light fiber for intra-tumor irradiation. In vivo, the fiber-mediated wPDT significantly induces tumor elimination with maximized therapeutic outcomes by irradiating the interior of the tumor. In addition, wPDT also has the advantage that its light source can be adapted to a wide range of photosensitizers (wavelength range 400-700 nm), whereas a laser of single wavelength can only target a specific photosensitizer. Conclusion: This method of using optical fiber to increase the tissue penetration of white light can greatly improve the therapeutic effect of AIE photosensitizers, which is needed for the treatment of large/deep tumors and holds great promise in cancer treatment.

Combining PD-L1 blockade with immunogenic cell death induced by AIE photosensitizer to improve antitumor immunity.

Immunogenic cell death (ICD) is considered an effective death mode to trigger immune response. However, the currently available efficient ICD inducers are quite limited. Endoplasmic reticulum (ER) stress is known as the precursor of ICD, which can be directly triggered by reactive oxygen species in situ. Herein, a novel photosensitizer (α-Th-TPA-PIO) based on phosphindole oxide, featuring aggregation-induced emission (AIE) is designed and prepared, which possesses good ability of hydroxyl radicals (HO•) generation. Besides, α-Th-TPA-PIO can selectively accumulate in ER and trigger ER stress under white light irradiation, further leading to effective ICD. Combining with anti-programmed death-ligand 1 (anti-PD-L1), the synergistic effect of photodynamic therapy (PDT) and immune checkpoint blockade can achieve a significantly enhanced inhibition effect on the growth of tumors and simultaneously provoke a systemic antitumor immune response. Notably, by adopting this therapeutic strategy to bilateral and metastatic tumor models, the growth of both primary and distant subcutaneous tumors can be successfully suppressed, and metastatic tumor can also be inhibited to some degree. Taken together, this work not only provides a novel ICD photoinducer based on PDT, but also brings about a useful immunomodulatory strategy to realize superior antitumor effect.

Antibacterial Theranostic Agents with Negligible Living Cell Invasiveness: AIE-Active Cationic Amphiphiles Regulated by Alkyl Chain Engineering.

To address the threat of bacterial infection in the following post-antibiotic era, developing effective antibacterial approaches is of utmost urgency. Theranostic medicine integrating diagnosis and therapy is a promising protocol to fight against pathogenic bacteria. But numerous reported antibacterial theranostic materials are disclosed to be trapped in the excessive invasiveness to living mammal cells, leading to false positives and possible biosafety risks. Herein, a series of cationic pyridinium-substituted phosphindole oxide derivatives featuring aggregation-induced emission are designed, and alkyl chain engineering is conducted to finely tune their hydrophobicity and investigate their bioaffinity preference for living mammal cells and pathogenic bacteria. Most importantly, an efficient theranostic agent (PyBu-PIO) is acquired that is free from living cell invasiveness with negligible cytotoxicity and yet holds a good affinity for Gram-positive bacteria, including drug-resistant strains, with a superior inactivating effect. Externally applying PyBu-PIO onto Gram-positive bacteria-infected skin wounds can achieve creditable imaging effects and successfully accelerate the healing processes with reliable biosafety. This work proposes living cell invasiveness as a criterion for antibacterial theranostic materials and provides important enlightenment for the design of antibacterial theranostic materials.

Improving Image-Guided Surgical and Immunological Tumor Treatment Efficacy by Photothermal and Photodynamic Therapies Based on a Multifunctional NIR AIEgen.

Multimodal therapy is attracting increasing attention to improve tumor treatment efficacy, but generally requires various complicated ingredients combined within one theranostic system to achieve multiple functions. Herein, a multifunctional theranostic nanoplatform based on a single aggregation-induced-emission luminogen (AIEgen), DDTB, is designed to integrate near-infrared (NIR) fluorescence, photothermal, photodynamic, and immunological effects. Intravenously injected AIEgen-based nanoparticles can efficiently accumulate in tumors with NIR fluorescence to provide preoperative diagnosis. Most of the tumors are excised under intraoperative fluorescence navigation, whereafter, some microscopic residual tumors are completely ablated by photodynamic and photothermal therapies for maximally killing the tumor cells and tissues. Up to 90% of the survival rate can be achieved by this synergistic image-guided surgery and photodynamic and photothermal therapies. Importantly, the nanoparticles-mediated photothermal/photodynamic therapy plus programmed death-ligand 1 antibody significantly induce tumor elimination by enhancing the effect of immunotherapy. This theranostic strategy on the basis of a single AIEgen significantly improves the survival of cancer mice with maximized therapeutic outcomes, and holds great promise for clinical cancer treatment.