Ce6 nanoassemblies:Molecular mechanism and strategies for combinational anticancer therapy Special Collection:Aggregation-Induced Processes and Functions

Nowadays,cancer has become the leading cause of death worldwide,driving the need for effective therapeutics to improve patient prognosis.Photodynamic therapy(PDT)has been widely applied as an antitumor modality,owing to its minimal invasiveness,localized tumor damage,and high safety profile.However,its efficacy is limited by poor stability of photosensitizers,inadequate tumor accumulation,and a complex tumor microenvironment.To overcome these challenges,extensive endeavors have been made to explore the co-assembly of the widely used photosensitizer chlorin e6(Ce6)with various functional small molecules to enhance pharmacodynamic activity.This review provides a comprehensive overview of current studies on Ce6-based nanoparticles for effective PDT and precise delivery of functional molecules.The self-assembly mechanism will be discussed in detail,with a focus on potential strategies for combinational therapy with PDT.

Phototriggered targeting of nanocarriers for drug delivery

Stimuli-triggered targeting of drug delivery systems can both increase the therapeutic efficacy and lower toxicity by selectively delivering drugs at target sites with high specificity and efficiency. Light is a convenient and powerful stimulus for use in such drug delivery systems because it is readily available and noninvasive and offers excellent spatiotemporal control. The power and wavelength of light can be finely tuned for different photoresponsive systems to achieve efficient targeting at the tissue, cellular, or subcellular levels. Here, we have reviewed the various mechanisms for phototriggered targeting （phototargeting） of drug nanocarriers. We have discussed the three main phototargeting strategies： （1） targeting ligand activation; （2） particle size reduction; and （3） blood vessel disruption.

Photo-triggered nucleus targeting for cancer drug delivery

Here,we report a strategy to deliver drug nanoparticles into cells with nucleus-targeting ability under a spatiotemporal control.The nanoparticles were constructed through self-assembly of photoresponsive prodrugs and free drugs.By incorporating a nucleus localization sequence in the system,drug nanoparticles could be delivered into nuclei upon visible light irradiation.The drug nanoparticles showed high drug loading capacity and specific nucleus-targeting ability,which efficiently killed cancer cells.This self-assembly strategy could be applied to other hydrophobic drugs and targeting ligands for photo-controlled organelle-targeted drug delivery.

Light-responsive nanomedicine for cancer immunotherapy

Immunotherapy emerged as a paradigm shift in cancer treatments, which can effectively inhibit cancer progression by activating the immune system. Remarkable clinical outcomes have been achieved through recent advances in cancer immunotherapy, including checkpoint blockades, adoptive cellular therapy, cancer vaccine, and tumor microenvironment modulation. However, extending the application of immunotherapy in cancer patients has been limited by the low response rate and side effects such as autoimmune toxicities. With great progress being made in nanotechnology, nanomedicine has been exploited to overcome biological barriers for drug delivery. Given the spatiotemporal control,light-responsive nanomedicine is of great interest in designing precise modality for cancer immunotherapy. Herein, we summarized current research utilizing light-responsive nanoplatforms to enhance checkpoint blockade immunotherapy, facilitate targeted delivery of cancer vaccines, activate immune cell functions, and modulate tumor microenvironment. The clinical translation potential of those designs is highlighted and challenges for the next breakthrough in cancer immunotherapy are discussed.

A green light-enhanced cytosolic protein delivery platform based on BODIPY-protein interactions

Development of cytosolic protein delivery platforms brings new possibilities for various incurable diseases.Strategies based on polymer/protein self-assembly have shown their potential in protein delivery.However,versatile photocontrolled platforms based on self-assembly for protein delivery are seldom reported.Herein,we report a boron-dipyrromethene(BODIPY)-modified polyamidoamine(PAMAM)with excellent photo-controllability and efficiency for the cytosolic delivery of various proteins.High serum stability was achieved by coating hyaluronic acid and human serum albumin on the surface of BODIPY-modified PAMAM/protein nanoparticles.The nanoparticles under green light irradiation allowed efficient intracellular delivery of multiple cargo proteins with different charges and molecular weights and promoted endosome escape.The study provides valuable guidance for the development of BODIPY derivative-based protein delivery systems and advances the research in intracellular protein delivery.

Carrier-free nanodrugs for stemness inhibition-enhanced photodynamic therapy

Cancer stem cell(CSC)has been considered a key driver of tumor growth,recurrence,and metastasis due to its self-renewal and tumor initiation capacities called stemness.Stemness is also responsible for the high resistance of CSC to current therapeutic strategies,including photodynamic therapy(PDT)and chemotherapy.In this study,a carrier-free nanodrug(designated as MKCe6 nanoparticle[NP])selfassembled by photosensitizer chlorin e6(Ce6)and stemness inhibitor MK-0752 was prepared for effective tumor repression.Stemness inhibition caused by MK-0752 could sensitize CSCs to PDT.Benefiting from the high drug-loading capacity and efficient cellular internalization,MKCe6 NPs exhibited good performance in PDT and stemness inhibition.In this way,effective tumor growth repression and tumorigenesis inhibition by MKCe6 NPs were observed both in vitro and in vivo.This self-delivery nanodrug for stemness inhibition-enhanced photodynamic therapy may provide new insights for clinical cancer therapy.

An AIE-active probe for efficient detection and high-throughput identification of outer membrane vesicles

Rapid detection and quantification of outer membrane vesicle(OMV)are of both scientific value and clinical implications.However,limited tools are available for investigations of OMVs.Herein,we report a novel fluorescent probe with aggregation-induced emission(AIE)characteristics,namely,OEO-TPE-MEM(OTM),for OMV detection.OTM emits faintly in an aqueous medium,but its fluorescence could be effectively turned on upon interacting with bacteria bodies and OMVs produced by Gram-negative bacteria.Notably,OTM could provide quantitative information on bacterial membrane remodeling and OMV secretion and be applied to high-throughput screening of OMV-inducing agents.This study presents a powerful AIE probe for imaging and quantitative analysis of bacteria envelop and derived OMVs,which might be applied for evaluating research and clinical antimicrobial materials in future studies.