The use of light as external energy for tumor therapy is a promising therapy model. However, a single type of phototherapy is limited by the complex microenvironment of tumor tissues and fails to effectively achieve tumor killing. For example, photodynamic therapy (PDT) leads to rapid O2 depletion during the generation of 1O2, triggering drug resistance mechanisms in cells, including the hypoxia-inducible factor (HIF-alpha) pathway. During photothermal therapy (PTT), cells synthesize large amounts of heat shock proteins to promote cellular recovery from thermal stimulation. Therefore, a multimodal phototherapy is needed to synergistically kill tumor cells. In this study, mesoporous silica coated Au nanoparticles with PTT and loaded IR780 with PDT were used, followed by encapsulation of tumor cell membranes with homologous targeting ability, under 808 nm laser irradiation, simultaneous PDT and PTT were achieved. The local high temperature generated by the PTT resulted in vasodilation to promote O2 supply in tumor site. The PDT led to protein and lipid peroxidation disrupting the repair mechanism of tumor cells. As the result of in vivo and in vitro experiments, synergistic therapy inhibited tumor cell growth and could be a potential strategy for tumor therapy.

Selective recognition of cancer-associated proteins (CAPs) by antibodies, followed by their delivery into the intracellular organelle, the lysosome, results in targeted degradation of CAPs and suppresses the growth of cancer cells. Translocating the antibody-CAP complex across the plasma membrane is, however, nontrivial. Phase-separating molecules are known to form membrane-translocating coacervates that can encapsulate proteins and transport them into the cytoplasm. Nevertheless, these coacervates generally lack the ability to guide the cargo to the lysosome. Here, we seal this gap and develop lysosome-targeting coacervates by tailoring a tetrapeptide into a phase-separating, coacervate-forming peptide. In the aqueous solution, the peptide derivative forms microdroplets, or coacervates, through liquid-liquid phase separation (LLPS), which spontaneously enter cells and colocalize with the lysosome; hence, these coacervates are referred to as Lysosome-Sorting Peptide Coacervates or LSP-Coa. We show that LSP-Coa can encapsulate proteins, facilitate the translocation of antibody-CAP complexes to the lysosome, and enable the degradation of membrane-bound CAPs - a mechanism we call Coacervate-mediated Lysosome-targeting Protein Degradation, or CoaLPD. Using the CoaLPD technology, we successfully degraded HER2 and EGFR in cancer cells and in tumor-bearing mice, showcasing its potential use as an anticancer treatment. The LSP-Coa system also increases the efficacy of PROTAC degradation through enhanced lysosomal uptake. Taken together, we present the design of lysosomal-targeting coacervates and demonstrate their use as vehicles for lysosome-specific antibody delivery and for the selective degradation of CAPs, thereby validating the CoaLPD strategy as a potential anticancer treatment.

Photothermal therapy (PTT) has garnered considerable attention for its noninvasive and localized treatment advantages. However, in response to PTT-induced hyperthermia, cancer cells increase the expression level of heat shock proteins (HSPs) and activate thermoresistance to shield themselves from heat-induced damage, thereby diminishing the efficacy of PTT. To overcome thermoresistance, here we have developed an on-demand responsive proteoliposome (PL) system. This system consists of PLs formed by a phospholipid conjugate of an elastin-like polypeptide (ELP) with vanadium oxide nanozymes (VOx NZs) incorporated in the lumen, referred to as VOx@ELP-PL. Upon photoirradiation, the enclosed VOx NZs generate a photothermal effect, inducing hyperthermia and enhancing HSP expression in cancer cells. Concurrently, as the temperature surpasses a critical threshold, ELP-PL undergoes liquid-liquid phase separation (LLPS) in situ, transitioning from a liposome state to ELP coacervate droplets. In the hyperthermic cancer cells, ELP coacervate droplets sequester and insulate the up-regulated HSPs, disrupting the thermoprotective response of thermoresistant cancer cells. Moreover, VOx@ELP-PL combines peroxidase-catalyzed generation of toxic hydroxyl radicals with coacervate droplet-mediated sequestration of HSPs, leading to potentiated immunogenic cell death both in vitro and in vivo. In a mouse model of colon cancer, intravenously injected VOx@ELP-PL showed marked tumor enrichment and resulted in highly effective cancer treatment. Altogether, this system presents a novel strategy to counteract thermoresistance by sequestering HSPs via LLPS of ELP-PL, thereby augmenting the effectiveness of PTT in cancer therapy.

Oncolytic bacteria are microorganisms with cytotoxic activity capable of lysing cancer cells while simultaneously activating both innate and adaptive immune responses to exert anti-tumor effects. However, the innate immune activation targeting oncolytic bacteria within the tumor microenvironment (TME) is a limiting factor. Here we find that the CD11b-targeting agonist GB1275 can modulate bacteria-immune interaction and inhibit the infiltration of CD11b⁺ innate immune cells such as neutrophils and macrophages, thereby suppressing the antimicrobial immune defenses in the TME in mice. This then avoids the clearance of oncolytic bacteria and increases the efficacy of bacteria-mediated tumor immunotherapy. Furthermore, the gemcitabine-loaded bacteria combined with GB1275 treatment activate innate immune responses in tumor, as mediated by Toll-like receptors (TLR), NOD-like receptors (NLR) and cGAS-STING pathways, while simultaneously enhancing dendritic cell (DC)-dependent antigen cross-presentation; this then upregulates the adaptive anti-tumor immune response and inhibits the growth of both subcutaneous and in situ pancreatic cancers in mouse tumor models. Our results therefore demonstrate that modulating innate immune responses while subsequently strengthening adaptive immune activation can significantly improve the efficacy of bacteria-mediated tumor immunotherapy. Cancer immune therapy by oncolytic bacteria triggers immune cell activation against the tumors, but the therapeutic effect may be compromised by ant-bacterial immune activity. Here the authors combine oncolytic bacteria with a CD11b agonist that alters the composition of tumor-infiltrating myeloid cells in mouse models to favor anti-tumor innate activation while preventing clearance of the bacteria.

The significant challenges pose by the high recurrence and metastasis rates of colorectal cancer (CRC) persist in its diagnosis and treatment. Activating innate immunity in CRC treatment has the potential to reduce drug resistance and side effects. Here, we develop a biomimetic platform by utilizing antimicrobial peptide-functionalized CRC cell membranes to encapsulate a cobalt-based metal-organic framework (C), hereby called peptide-functionalized camouflage C (PfCC). When injected into tumour-bearing mice, PfCC will degrade under the acidic condition of the tumour microenvironment and release cobalt ions, which react with endogenous H2S to generate black stellate precipitates with good photothermal properties, recruiting NK cells and mitigates the immunosuppressive tumour-microenvironment. Simultaneously, the degradation of PfCC will release structure-protected antimicrobial peptides, inhibiting harmful bacteria, such as Desulfovibrio, and reducing H2S production. The abovementioned synergistic top-down regulation of H2S promote the polarization of macrophages and further activates the innate immune response. Moreover, experiments including the convex hull algorithm from AI deep learning of the segment anything model indicate that PfCC exhibites the most effective therapeutic effect compared with the single H2S-regulated therapeutic modality. Taken together, PfCC represents a potential anti-cancer therapy for CRC with the combined effect of immune-regulation and the regulation of the gut flora.

Rationale: Synthetic molecules, meticulously designed according to the "sticker-and-spacer model", tend to form coacervates via liquid-liquid phase separation (LLPS), thereby acquiring properties beyond their discrete and soluble states. However, natural compounds, such as those from traditional Chinese medicines (TCMs), are not known to undergo phase separation. In this study, we demonstrate that curcumin, the active ingredient in the spice turmeric, forms phase-separated fluorescent coacervates when diluted from a concentrated organic-solvent solution into an aqueous solution. Methods: Curcumin coacervates were formed by diluting a concentrated stock solution in organic solvents into the aqueous solution. We utilized the coacervate droplets to encapsulate and transport various biomacromolecules, such as proteins and nucleic acids, across the plasma membrane into the cell. Supramolecular interaction between β-cyclodextrin (β-CD) and curcumin disassembles curcumin coacervates, leading to cargo release in the cytosol. Results: Intravenously injected curcumin coacervates spontaneously enrich in the tumor tissue in tumor-bearing BALB/c mice. Subsequent intratumoral injection of β-CD significantly enhances anticancer effects in mice, demonstrating the efficacy of coacervate-mediated siRNA drug delivery and supramolecular-interaction-responsive intracellular release in vivo. Conclusions: Taken together, we report here the coacervate-forming properties of the natural TCM compound curcumin, presenting a unique strategy for controlling coacervate states through supramolecular interactions with β-cyclodextrin in vitro and in vivo, along with the unexplored potential of curcumin coacervate-mediated siRNA delivery to enhance pyroptosis.

The endoplasmic reticulum (ER) serves as a critical target for diverse therapeutics. Developing novel ER delivery strategies is essential for enhancing drug efficacy. Current efforts focus on tissue and cellular-level drug delivery, while subcellular-targeting remains confined to lysosomal escape into the cytosol. Although approaches employing STING agonists, E3 viral peptides as targeting ligands have been explored, the “last-mile” delivery from cytosol to ER persists as a challenge due to unclear mechanisms and low efficiency. We employ the ribosome as a drug carrier to exploit its trafficking mechanism toward the ER during translation, enabling efficient delivery of drugs. We used levofloxacin as a ribosome lead molecule and synthesized Lc-RCy by coupling it with RGD and cyanine dye (Cy). Lc-RCy effectively binds ribosomes and reaches the ER during protein translation. Subsequent photodynamic treatment near the ER using the photodynamic effect of Cy induced significant immunogenic cell death and inhibited tumor growth.

Hydrazine is a highly toxic reducing agent whose sensitive detection is important for environmental monitoring. In this work, sunflower sporopollenin exine capsules (SEC) are used as a natural porous support...

Caspase-3 plays a critical role in apoptosis and has been regarded as a key marker in apoptosis-related disease diagnosis and therapy. However, the Caspase-3 detection in complex biological environments remains challenging due to the existence of various interferences. To solve this challenge, an antifouling nanopore biosensor is constructed by integrating distearoylphosphatidyl ethanolamine-poly(ethylene glycol) (DSPE-PEG) and a Caspase-3-targeted peptide in a single glass nanopore, and it has been successfully used for the detection and analysis of Caspase-3 protease in complex biological environments. Contact angle, electrochemical, and confocal imaging characterizations confirm the good antifouling ability of the biosensor. The sensing performance of the biosensor was characterized by the change in the nanopore's rectified ionic current. The results indicated that the antifouling biosensor has a good detection performance for Caspase-3, with a detection limit of 0.46 ng/mL, and excellent selectivity against interfering proteins.

Systemic chemotherapy is the main approach for treating colorectal cancer (CRC), but its side effects are significant. Therefore, developing localized delivery systems is crucial. Natural sunflower pollen shells are characterized by low cost, high drug loading capacity, corrosion resistance and good biocompatibility in short-term were utilized in the design of a bio-mimetic oral drug delivery system to achieve combined chemotherapy and immunotherapy for colorectal cancer. The system utilizes the pollen shell cavity to load the chemotherapeutic drug doxorubicin (DOX) and employs manganese dioxide (MnO2) nanoparticles deposited on the surface to modulate the tumor immune micro-environment. An outer chitosan coating is applied for encapsulation, enabling precise responsive drug release in the colorectal region. In vitro and in vivo experimental results demonstrate that the system exhibits excellent gastrointestinal stability, significantly enhances intestinal adhesion and retention capabilities, successfully induces immunogenic cell death (ICD), and may be associated with the activation of the cGAS-STING pathway, thereby effectively inhibiting tumor growth. This study provides a novel strategy for developing efficient colorectal-targeted delivery platforms.

Triple-negative breast cancer (TNBC) exhibits aberrant copper accumulation that promotes tumor progression and metastasis. Targeting copper homeostasis, particularly at the mitochondrial level, represents a promising yet underexplored therapeutic strategy. Herein,...

Macrophages show great potential for application in cellular immunotherapy, but are limited by immune checkpoints (ICBs). Immune checkpoint inhibitors (ICIs) can effectively block immune escape pathways and alleviate immune suppression in the tumor microenvironment (TME). Here, we constructed hypoxia response bacteria (HRB) that specifically expressed CD47 antibody (aCD47) under hypoxic conditions in the TME, enabling the in situ synthesis of ICIs at the tumor site. In addition, this study further prepared responsive liposomes for encapsulating the STING agonist cGAMP and modified them by covalent attachment to the HRB surface to form the composite material HRB@LC. This composite system can synergistically block CD47-SIRPα-mediated immune escape and activate the STING signal pathway, thereby enhancing systemic antitumor immune responses and significantly improving the efficacy of immunotherapy.

In this work, the performance of Pd@Cu2O with a core-shell structure for enzyme-free electrochemical glucose sensing is systematically investigated.

Cuproptosis, a recently identified copper-dependent form of regulated cell death, offers unique advantages for cancer therapy but suffers from poor tumor targeting, systemic toxicity, and limited immune activation. Meanwhile, immune checkpoint therapy (ICT) can enhance antitumor immunity but often faces resistance and adverse effects when used alone. To address these challenges, we developed a hybrid therapeutic platform (HRB@Cur@ZIF) that integrates engineered Escherichia coli with curcumin-loaded, copper-based ZIF-8 nanoparticles. The engineered bacteria selectively colonize hypoxic tumor regions and secrete anti-CD47 antibodies to relieve immune suppression, while the acid-responsive nanoparticles release copper ions and curcumin to trigger localized cuproptosis and amplify oxidative stress. This spatiotemporally coordinated strategy enables precise tumor targeting, potent immuno modulation, and efficient tumor cell killing. Both in vitro and in vivo studies demonstrate strong tumor growth inhibition, suppression of metastasis, and excellent biosafety, with complete tumor regression in a subset of treated mice. Mechanistically, HRB@Cur@ZIF promotes dendritic cell maturation, macrophage M1 polarization, and cytotoxic T cell infiltration, while downregulating cuproptosis regulators FDX1 and LIAS. This work establishes a clinically translatable strategy that synergizes cuproptosis and immunotherapy for precision cancer treatment.

Rapid and ultrasensitive detection of botulinum neurotoxin serotype A (BoNT/A), the most lethal known toxin, is critical for food safety and clinical diagnosis. Herein, we present a novel visual detection platform integrating a programmable DNA-guided nuclease, mutant Pyrococcus furiosus Argonaute (mPfAgo), with a pregnancy test strip (PTS), collectively termed mPfAgo-PTS. In this design, BoNT/A is first captured by an immunocomplex functionalized with a DNA tag. After amplification, the resulting amplicon directs mPfAgo to cleave a customized probe conjugated to human chorionic gonadotropin (hCG), thereby releasing free hCG for visual readout on the PTS. This cascaded signal transduction and amplification strategy enables the mPfAgo-PTS platform to detect BoNT/A down to 10 fg/mL within 60 min, representing a 1000-fold improvement in sensitivity over the gold-standard mouse bioassay. High precision and sensitivity validate its robustness and versatility for practical applications in food safety and clinical screening.

In clinical practice, surgical removal of tumors often leaves behind small tumors and circulating tumor cells, increasing the risk of metastasis and recurrence, which seriously affects treatment outcomes. Immunotherapy activates the immune system to monitor and inhibit tumor metastasis and recurrence long-term. However, inflammatory microenvironments at surgical sites lead to immunosuppressive tumor-associated macrophages (TAMs), causing immune evasion. Additionally, tumor cells overexpress the immune checkpoint CD47, further weakening the phagocytic and cytotoxic functions of macrophages. Here, the bacterial outer membrane vesicles (OMV) hitchhiking on neutrophils are utilized to precisely deliver immune checkpoint blockade antibodies to the tumor resection site. Escherichia coli is reprogrammed to express CD47 antibody and used to extract CD47 antibody-containing OMV, followed by insertion of Ce6 photosensitizer into the membrane (OC47-Ce6). Purified autologous neutrophils phagocytose and carry OC47-Ce6 for precise targeting to the postoperative tumor resection site, mediating tumor cell killing, aCD47 release, and tumor-associated antigen presentation by light. In vitro and in vivo experiments demonstrate that OC47-Ce6 enhances TAM phagocytic function through TAM polarization and CD47 blockade. This approach effectively activates T-cell anti-tumor immune responses and significantly reduces the risk of postoperative tumor recurrence and metastasis.

Tumor immune checkpoint therapy (ICT) aims to block immune escape signals between tumor and immune cells. However, low delivery efficiency of immune checkpoint inhibitors (ICIs), narrow single-target approach, and reduced responsiveness notably hinder clinical development of ICT. Here, we developed a nanoliposome-bacteria hybrid system that acts as an antibody (Ab) factory, enabling precise tumor targeting and macrophage activation in hypoxic environments. We reprogrammed attenuated Escherichia coli MG1655 to synthesize CD47 antibodies (aCD47) in response to hypoxic tumor microenvironments while surface conjugating with redox-responsive macrophage colony-stimulating factor-loaded liposomes. This system leverages bacterial tropism to enhance macrophage infiltration and polarization. The low oxygen levels trigger in situ aCD47 expression, blocking the "do not eat me" signal and boosting macrophage antitumor activity. In addition, macrophage antigen presentation activates CD8+CD3+ T cells, amplifying systemic antitumor immunity. Analysis of the gut microbiome shows reduced pathogenicity and improved intestinal tolerance with increased probiotics.

Sonodynamic therapy (SDT) exhibits high tissue penetration and negligible radiation damage to normal tissue, but it hampered by the limited oxygen in tumor, which can be potentiated via improving oxygen metabolism and increasing oxygen utilization efficiency. Herein, a multifunctional biomimetic nanocarrier (VI@R-T) is fabricated by encapsulating vanadium-based nanozyme (VOx) with dual enzyme activity and sonosensitizer indocyanine green (ICG) into the mitochondria-targeted erythrocyte vesicle. The nanocarrier can be targeted to the mitochondria, where the enzyme in red blood cell membrane catalyzed endogenous H2O2 to increase O2 content for alleviating hypoxia. Meanwhile, nanozyme exhibits the NADH oxidase (NOX) activity affecting the nicotinamide adenine dinucleotide/flavin adenine dinucleotide (NADH/FAD) balance in the cellular oxidative phosphorylation, which impairs the mitochondrial electron transport chain and reduces intracellular oxygen consumption, thereby significantly improving tumor oxygen metabolism and the efficacy of SDT. In addition, nanozyme also shows peroxide-like activity in tumor microenvironment (TME), and generates highly toxichydroxyl radical (OH) for ROS-amplifying oxidative stress. Deep-hypothermia potentiated 2D/3D autofluorescence imaging also monitored the nanocarrier effectively disrupt the balance of NADH/FAD in the tumor. This work provides anew approach for designing ROS-based biomimetic nanomedical platform for tumor hypoxia relief.

Low-molecular-weight compounds of certain structural features may form coacervates through liquid-liquid phase separation (LLPS). These coacervates can enter mammalian cells and affect cellular physiology. Controlling the properties of the coacervates inside cells, however, is a challenge. Here, we report photochemical reactions of spiropyran (SP)-based coacervates with two wavelengths of light, in vitro, in the cell, and in animals, generating reactive oxygen species (ROS) for photo-controlled cell killing. We identify an SP-containing compound, SP-PEG8-SP, that forms coacervates (SP-C) in the aqueous solution. Photo illumination by a UV light triggers the isomerization of SP to merocyanine (MC), switching SP-C to the fluorescent coacervates MC-C. A visible light converts MC-C back to SP-C and induces ROS generation. Notably, coacervate formation increases the compound's ROS generation efficiency. The SP-C/MC-C coacervate system (collectively called spiropyran coacervates) can spontaneously enter cells, and a dual-wavelength-controlled reversible on/off switch and spatiotemporal-resolved ROS production is realized within the cytoplasm. Light-induced ROS generation leads to cytotoxicity to cancer cells, tumor organoids, and tumors in vivo, supporting spiropyran coacervates' potential use as coacervate photosensitizers in photodynamic therapies.

The unique physiological characteristics and complexity of tumor, in addition to drug resistance result in traditional therapies, such as chemotherapy and radiotherapy, being unable to achieve complete elimination of cancer cells. Meanwhile, the emerging immunotherapy suffers from a low patient response rate. Bacterial therapies are highly targeted. Bacteria can penetrate deep into the tumor and show good tumor inhibition. However, natural bacteria have the limitation of high toxicity and inability to meet the demand for efficient therapeutics. Recent advances in synthetic biology and materials science relate to the safety and efficacy of bacterial therapeutics, promising to develop engineered bacteria with low toxicity and complex therapeutic functions. Engineered bacteria that express anticancer drug molecules can target the tumor region, synthesizing and releasing payloads in response to internal and external stimuli. This process leads to the regression of the tumor and the effective inhibition of recurrence. This review outlines the recent advancements in the field of engineered bacteria research, particularly focusing on their applications in anti-tumor therapy. It also includes the advantageous features and mechanisms of engineered bacteria therapy, synthetic biology modification methods, and future challenges and directions of engineered bacteria therapy.