Biomedical Application of Porphyrin-Based Amphiphiles and Their Self-Assembled Nanomaterials.

Porphyrins have been vastly explored and applied in many cutting-edge fields with plenty of encouraging achievements because of their excellent properties. As important derivatives of porphyrins, porphyrin-based amphiphiles (PBAs) not only maintain the advanced properties of porphyrins (catalysis, imaging, and energy transfer) but also possess self-assembly and encapsulation capability in aqueous solution. Accordingly, PBAs and their self-assembles have had important roles in diagnosing and treating tumors and inflammation lesions in vivo, but not limited to these. In this article, we introduce the research progress of PBAs, including their constitution, structure design strategies, and performances in tumor and inflammation lesion diagnosis and treatments. On that basis, the defects of synthesized PBAs during their application and the possible effective strategies to overcome the limitations are also proposed. Finally, perspectives on PBAs exploration are updated based on our knowledge. We hope this review will bring researchers from various domains insights about PBAs.

Seven-layer analysis model of an optical waveguide excitation fluorescence microscopy.

In this paper, an optical waveguide evanescent field fluorescence microscopy is studied. Based on Maxwell's equation, a seven-layer theoretical analysis model is developed for the evaluation of an optical waveguide excitation fluorescence microscopy. The optical waveguide excitation fluorescence microscopy structure is systematically and comprehensively analysed at the wavelengths of 488, 532 and 646 nm for fluorescent dyes. The analysis results provide some useful suggestions, which will be beneficial to the research of an optical waveguide evanescent field fluorescence microscopy.

Recent Research Progress of 19 F Magnetic Resonance Imaging Probes: Principle, Design, and Their Application.

Visualization of biomolecules, cells, and tissues, as well as metabolic processes in vivo is significant for studying the associated biological activities. Fluorine magnetic resonance imaging (19 F MRI) holds potential among various imaging technologies thanks to its negligible background signal and deep tissue penetration in vivo. To achieve detection on the targets with high resolution and accuracy, requirements of high-performance 19 F MRI probes are demanding. An ideal 19 F MRI probe is thought to have, first, fluorine tags with magnetically equivalent 19 F nuclei, second, high fluorine content, third, adequate fluorine nuclei mobility, as well as excellent water solubility or dispersity, but not limited to. This review summarizes the research progresses of 19 F MRI probes and mainly discusses the impacts of structures on in vitro and in vivo imaging performances. Additionally, the applications of 19 F MRI probes in ions sensing, molecular structures analysis, cells tracking, and in vivo diagnosis of disease lesions are also covered in this article. From authors' perspectives, this review is able to provide inspirations for relevant researchers on designing and synthesizing advanced 19 F MRI probes.

Non-coplanar misalignment optical waveguide cantilever sensor with a monotonic response in a large operation range.

This paper reports a non-coplanar misalignment optical waveguide cantilever sensor realizing a monotonic response with a large operation range. A 1×2 Y-branch optical power splitter cantilever structure was designed, and one of the branches was reduced in thickness at the end, as a non-coplanar structure with respect to another. The misalignment coupling of the two branches due to the thickness of one branch leads to a monotonic response of an optical waveguide cantilever sensor. The simulation results showed a monotonic response with a sensitivity of 6×10-4 n m -1 in a large operation range of -1 to 1 µm.

Segregated Nanocompartments Containing Therapeutic Enzymes and Imaging Compounds within DNA-Zipped Polymersome Clusters for Advanced Nanotheranostic Platform.

Nanotheranostics is an emerging field that brings together nanoscale-engineered materials with biological systems providing a combination of therapeutic and diagnostic strategies. However, current theranostic nanoplatforms have serious limitations, mainly due to a mismatch between the physical properties of the selected nanomaterials and their functionalization ease, loading ability, or overall compatibility with bioactive molecules. Herein, a nanotheranostic system is proposed based on nanocompartment clusters composed of two different polymersomes linked together by DNA. Careful design and procedure optimization result in clusters segregating the therapeutic enzyme human Dopa decarboxylase (DDC) and fluorescent probes for the detection unit in distinct but colocalized nanocompartments. The diagnostic compartment provides a twofold function: trackability via dye loading as the imaging component and the ability to attach the cluster construct to the surface of cells. The therapeutic compartment, loaded with active DDC, triggers the cellular expression of a secreted reporter enzyme via production of dopamine and activation of dopaminergic receptors implicated in atherosclerosis. This two-compartment nanotheranostic platform is expected to provide the basis of a new treatment strategy for atherosclerosis, to expand versatility and diversify the types of utilizable active molecules, and thus by extension expand the breadth of attainable applications.

pH-Responsive Pickering Foams Generated by Surfactant-Free Soft Hydrogel Particles.

Pickering foams are foams stabilized by particles and are generally known to have good stability. A special subclass of particle-stabilized foams includes stimuli-responsive Pickering foams that can be formed or deconstructed by applying an external stimuli or changing the environmental conditions; such intelligent particles could find use in many practical applications. Here, we synthesized surfactant-free biocompatible poly[2(diethylamino)ethyl methacrylate] (PDEAEMA) hydrogel particles (HGPs) by emulsion polymerization. The morphology, structure, and surface charge of the HGPs were characterized by TEM, DLS, and the zeta potential, respectively. We have observed that the pH values of the aqueous solution have a strong influence on the formation of the Pickering foams in the presence of PDEAEMA HGPs. Namely, at pH values ≤4.0 no Pickering foams were produced, while at pH values >4.0 stable Pickering foams were formed. Moreover, the height, size and bubble size distribution of Pickering foams are strongly influenced by the pH values of aqueous solution and PDEAEMA HGPs concentration. The formed Pickering foams in basic aqueous solution can all be conveniently deconstructed by changing the pH values to below 4.0. Interestingly, the dried lamellas of the Pickering foams were constituted by either monolayers or multilayers of PDEAEMA HGPs as demonstrated by SEM.

Contrasting Mechanisms of Spontaneous Adsorption at Liquid-Liquid Interfaces of Nanoparticles Constituted of and Grafted with pH-Responsive Polymers.

Elucidating the mechanisms responsible for spontaneous adsorption of nanoparticles (NPs) at interfaces is important for their application as emulsifiers, bubble stabilizers, or foaming agents. In order to investigate the key factors that control the spontaneous adsorption of NPs at liquid-liquid interfaces, we synthesized seven different types of NPs from pH-responsive polymers poly(2-(diethylamino)ethyl methacrylate) (PDEAEMA) and poly(2-dimethylamino)ethyl methacrylate) (PDMAEMA) via surfactant-free emulsion polymerization or via "grafting from" polystyrene (PS) NPs. The dynamic interfacial tension (IFT) measurements at the toluene-water (Tol-H2O) interface reveal that when PDEAEMA and PDMAEMA are grafted from the surface of PS NPs the solubility of the grafted pH-responsive polymers in toluene is the key factor determining the NPs' interfacial adsorption. Under acidic conditions (pH < 6.0), PDEAEMA and PDMAEMA are protonated and show no solubility in toluene, and as a result, the grafted NPs do not adsorb at the Tol-H2O interface. Oppositely, under basic conditions (pH > 7.0), PDMAEMA dissolves in toluene and therefore the PDMAEMA-grafted NPs can adsorb at the Tol-H2O interface. Interestingly, when NPs are constituted of PDEAEMA, they can adsorb spontaneously at the Tol-H2O interface under acidic conditions (pH < 6.0) but not under basic conditions (pH > 7.0). In this case, the key factor determining the NPs' spontaneous adsorption at the Tol-H2O interface is the degree of softness of the NPs rather than the solubility of PDEAEMA in toluene. Furthermore, we found that the adsorption of NPs constituted of PDEAEMA- (pH 2.0-6.0) and PDMAEMA-grafted PS NPs (pH 7.0-10.0) at the Tol-H2O interface is a combination of diffusion-controlled and energy-barrier-controlled. The opposite trends observed for the interfacial attachment Δ E and activation energies Ea for the "constituted of" and "grafted from" NPs with pH suggest an opposite mechanisms of adsorption at the Tol-H2O interface. Finally, the synthesized NPs prove to be effective emulsifiers, where the phase of the Pickering emulsions can be changed dynamically by pH adjustment.

Modeling the Interfacial Energy of Surfactant-Free Amphiphilic Janus Nanoparticles from Phase Inversion in Pickering Emulsions.

Determining the interfacial energy of nanoparticles is very challenging via traditional methods that first require measuring the contact angle of several liquids of a sessile drop on pellets or capillary rise in powder beds. In this work, we propose an alternative way to model the interfacial energy of nanoparticles directly from emulsion phase inversion data in Pickering emulsions. This could establish itself as a universal and facile way to determine the polarity of nanoparticles relative to a series of standard particles without the need to measure contact angles. Pickering emulsions of several oils in water were generated with a series of snowman-like Janus nanoparticles (JNPs), whose polarity gradually increased with the size of the more polar lobe. Depending on the oil to water ratio and the JNPs lobe size, oil-in-water (o/w) or water-in-oil (w/o) Pickering emulsions were obtained and the affinity of the JNPs to either water or oil can be inferred from the evolution of the emulsion phase inversion curves with these parameters. We further demonstrate that by adopting a simple model for the work of adhesion of JNPs with the water and oil phases, one can quantitatively calculate the relative interfacial energy change of the JNPs with the liquid. In addition, a knowledge of the interfacial energy of nanoparticles is useful for employing these in suspension polymerization to create surface nanostructured materials. The o/w and w/o Pickering emulsions obtained from monomers, such as styrene, could be polymerized, resulting in colloidosomes or hollow-like materials. The hollow materials exhibited a rather high volume storage capacity for the aqueous phase for extended periods of time, which could be released upon microwaving, making them ideal for use in long-term storage applications of various water-soluble actives.

DNA-Mediated Self-Organization of Polymeric Nanocompartments Leads to Interconnected Artificial Organelles.

Self-organization of nanocomponents was mainly focused on solid nanoparticles, quantum dots, or liposomes to generate complex architectures with specific properties, but intrinsically limited or not developed enough, to mimic sophisticated structures with biological functions in cells. Here, we present a biomimetic strategy to self-organize synthetic nanocompartments (polymersomes) into clusters with controlled properties and topology by exploiting DNA hybridization to interconnect polymersomes. Molecular and external factors affecting the self-organization served to design clusters mimicking the connection of natural organelles: fine-tune of the distance between tethered polymersomes, different topologies, no fusion of clustered polymersomes, and no aggregation. Unexpected, extended DNA bridges that result from migration of the DNA strands inside the thick polymer membrane (about 12 nm) represent a key stability and control factor, not yet exploited for other synthetic nano-object networks. The replacement of the empty polymersomes with artificial organelles, already reported for single polymersome architecture, will provide an excellent platform for the development of artificial systems mimicking natural organelles or cells and represents a fundamental step in the engineering of molecular factories.

Polarity Reversal in Homologous Series of Surfactant-Free Janus Nanoparticles: Toward the Next Generation of Amphiphiles.

The ability to finely tune the amphiphilic balance of Janus nanoparticles (JNPs) could represent a step forward toward creating the next generation of solid-state amphiphiles with significant potential for applications. The inherent amphiphilicity of JNPs stemming from an intrinsic polarity contrast between two surface regions is well-acknowledged, but remained difficult to demonstrate experimentally in the absence of surfactants and stabilizers. We have designed two homologous series of surfactant-free polymeric JNPs starting from polystyrene (PS) seed nanoparticles (NPs) on which we grew Janus lobes of different sizes via seed polymerization and phase separation of the 3-(triethoxysilyl)propyl-methacrylate (3-TSPM) monomer. The two series differ only by the radical initiator used in the seed polymerization: polar ionic ammonium persulfate (APS) vs nonpolar oil-soluble 2,2'-azobis(2-methylpropionitrile) (AIBN). To compare the two series, we employed them in the emulsification of water with heptane or molten paraffin wax. A polarity reversal of the JNPs within AIBN-JNP series could be observed from the catastrophic and transitional emulsion phase inversions and occurred when the more polar lobe was larger than the nonpolar seed PS lobe. Furthermore, the AIBN-JNPs appeared to be amphiphilic and adopt preferred orientation within the monolayer at the oil/water interface. We therefore demonstrated that in the absence of surfactants the amphiphilicity of the JNPs depends not only on the relative size of the lobes, but also on the surface polarity contrast, which can be tuned by changing the nature of radical initiator.

Hybrid polymer-lipid films as platforms for directed membrane protein insertion.

Hybrids composed of amphiphilic block copolymers and lipids constitute a new generation of biological membrane-inspired materials. Hybrid membranes resulting from self-assembly of lipids and polymers represent adjustable models for interactions between artificial and natural membranes, which are of key importance, e.g., when developing systems for drug delivery. By combining poly(dimethylsiloxane)-block-poly(2-methyl-2-oxazoline) amphiphilic copolymers (PDMS-b-PMOXA) with various phospholipids, we obtained hybrid films with modulated properties and topology, based on phase separation, and the formation of distinct domains. By understanding the factors driving the phase separation in these hybrid lipid-polymer films, we were able to use them as platforms for directed insertion of membrane proteins. Tuning the composition of the polymer-lipids mixtures favored successful insertion of membrane proteins with desired topological distributions (in polymer or/and lipid regions). Controlled insertion and location of membrane proteins in hybrid films make these hybrids ideal candidates for numerous applications where specific spatial functionality is required.

Filling polymersomes with polymers by peroxidase-catalyzed atom transfer radical polymerization.

Polymersomes that encapsulate a hydrophilic polymer are prepared by conducting biocatalytic atom transfer radical polymerization (ATRP) in these hollow nanostructures. To this end, ATRPase horseradish peroxidase (HRP) is encapsulated into vesicles self-assembled from poly(dimethylsiloxane)-block-poly(2-methyl-2-oxazoline) (PDMS-b-PMOXA) diblock copolymers. The vesicles are turned into nanoreactors by UV-induced permeabilization with a hydroxyalkyl phenone and used to polymerize poly(ethylene glycol) methyl ether acrylate (PEGA) by enzyme-catalyzed ATRP. As the membrane of the polymersomes is only permeable for the reagents of ATRP but not for macromolecules, the polymerization occurs inside of the vesicles and fills the polymersomes with poly(PEGA), as evidenced by (1) H NMR. Dynamic and static light scattering show that the vesicles transform from hollow spheres to filled spheres during polymerization. Transmission electron microscopy (TEM) and cryo-TEM imaging reveal that the polymersomes are stable under the reaction conditions. The polymer-filled nanoreactors mimic the membrane and cytosol of cells and can be useful tools to study enzymatic behavior in crowded macromolecular environments.

Poly(N-isopropylacrylamide-co-tris-nitrilotriacetic acid acrylamide) for a combined study of molecular recognition and spatial constraints in protein binding and interactions.

Many biological processes require precise regulation and synergy of proteins, and consequently involve molecular recognition and spatial constraints between biomolecules. Here, a library of poly(N-isopropylacrylamide-co-tris-nitrilotriacetic acid acrylamide) (PNTs) has been synthesized and complexed with Cu(2+) in order to serve as models for investigation of the combined effects of molecular recognition and spatial constraints in biomolecular interactions. The average distance between Cu(2+)-trisNTA binding sites in PNTs polymers was varied from 4.3 to 31.5 nm by adjusting their trisNTA contents. His tag (His6), His-tagged enhanced yellow fluorescent protein (His6-eYFP), and His6-tagged collagenase G (His6-ColG), with sizes ranging from 1 to 11 nm, were used as models to assess whether the binding ability is influenced by a cooperative topology based on molecular recognition interactions with Cu(2+)-trisNTA binding sites, and spatial constraints created by decreasing average distance between trisNTAs. His-tagged molecules bound to all PNTs polymers due to their molecular recognition interaction involving histidines and Cu(2+)-trisNTA pockets, but with a binding ability that was highly modulated by the average distance between the trisNTA binding sites. Small molecular mass molecules (His6) exhibit a high binding ability to all PNTs polymers, whereas his-tagged proteins bind to PNTs efficiently only when the average distance between trisNTA binding sites is larger than the protein dimensions.

A polymeric 1H/19F dual-modal MRI contrast agent with a snowman-like Janus nanostructure.

Magnetic resonance imaging (MRI) has emerged as a pivotal tool in contemporary medical diagnostics, offering non-invasive and high-resolution visualization of internal structures. Contrast agents are essential for enhancing MRI resolution, accurate lesion detection, and early pathology identification. While gadolinium-based contrast agents are widely used in clinics, safety concerns have prompted exploration of metal-free alternatives, including fluorine and nitroxide radical-based MRI contrast agents. Fluorine-containing compounds exhibit excellent MRI capabilities, with 19F MRI providing enhanced resolution and quantitative assessment. Nitroxide radicals, such as PROXYL and TEMPO, offer paramagnetic properties for MRI contrast. Despite their versatility, nitroxide radicals suffer from lower relaxivity values (r1) compared to gadolinium. Dual-modal imaging, combining 1H and 19F MRI, has gained prominence for its comprehensive insights into biological processes and disease states. However, existing dual-modal agents predominantly utilize gadolinium-organic ligands without incorporating nitroxide radicals. Here, we introduce a novel dual-modal MRI contrast agent (J-CA) featuring a Janus asymmetric nanostructure synthesized via seeded emulsion polymerization and post-modification. J-CA demonstrates excellent in vitro and in vivo performance in both 19F and 1H MRI, with a T2 relaxation time of 5 ms and an r1 value of 0.31 mM-1 s-1, ensuring dual-modal imaging capability. Moreover, J-CA exhibits superior biocompatibility and organ targeting, making it a promising candidate for precise lesion imaging and disease diagnosis. This work introduces a new avenue for metal-free dual-modal MRI, addressing safety concerns associated with traditional contrast agents.

Imidazolium-Based Main-Chain Copolymers With Alternating Sequences for Broad-Spectrum Bactericidal Activity and Eradication of Bacterial Biofilms.

In response to the escalating challenge of bacterial drug resistance, the imperative to counteract planktonic cell proliferation and eliminate entrenched biofilms underscores the necessity for cationic polymeric antibacterials. However, limited efficacy and cytotoxicity challenge their practical use. Here, novel imidazolium-based main-chain copolymers with imidazolium (PIm+) as the cationic component are introduced. By adjusting precursor molecules, hydrophobicity and cationic density of each unit are fine-tuned, resulting in broad-spectrum bactericidal activity against clinically relevant pathogens. PIm+1 stands out for its potent antibacterial performance, with a minimum inhibitory concentration of 32 µg mL-1 against Methicillin-resistant Staphylococcus aureus (MRSA), and substantial biofilm reduction in Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) biofilms. The bactericidal mechanism involves disrupting the outer and cytoplasmic membranes, depolarizing the cytoplasmic membrane, and triggering intracellular reactive oxygen species (ROS) generation. Collectively, this study postulates the potential of imidazolium-based main-chain copolymers, systematically tailored in their sequences, to serve as a promising candidate in combatting drug-resistant bacterial infections.

Holmium (III)-doped multifunctional nanotheranostic agent for ultra-high-field magnetic resonance imaging-guided chemo-photothermal tumor therapy.

Ultra-high-field (UHF) MRI has shown great advantages over low-field magnetic resonance imaging (MRI). Despite being the most commonly used MRI contrast agents, gadolinium chelates perform poorly in high magnetic fields, which significantly weakens their T1 intensity. In comparison, the rare element Holmium (Ho)-based nanoparticles (NPs) have demonstrated great potential as T2-weighted MRI contrast agents in UHF MRI due to their extremely short electron relaxation times (∼ 10-13s). In this study, a multifunctional nanotherapeutic probe was designed for UHF MRI-guided chemotherapy and photothermal therapy. The Ho (III)-doped mesoporous polydopamine (Ho-MPDA, HM) nanosphere was loaded with the chemotherapeutic drug mitoxantrone (MTO) and then coated with 4T1 cell membranes to enhance active targeting delivery to breast cancer. The prepared nanotherapeutic probe MTO@HMM@4T1 (HMM@T) exhibited good biocompatibility, high drug-loading capability and great potential as Ho (III)-based UHF MRI contrast agents. Moreover, the biodegradation of HMM@T in response to the intratumor pH and glutathione (GSH) promotes MTO release. Near-infrared (NIR) light irradiation of HM induced photothermal therapy and further enhanced drug release. Consequently, HMM@T effectively acted as an MRI-guided tumor-targeting chemo-photothermal therapy against 4T1 breast cancer. STATEMENT OF SIGNIFICANCE: Ultra-high-field (UHF) MRI has shown great advantages over low-field magnetic resonance imaging (MRI). Although gadolinium chelates are the most commonly used MRI contrast agents in clinical practice, they exhibit a significantly decreased T1 relaxivity at UHF. Holmium exhibits outstanding UHF magnetic resonance capabilities in comparison with gadolinium chelates currently used in clinic. Herein, a theranostic nanodrug (HMM@T) was designed for UHF MRI-guided chemo-photothermal therapy. The nanodrug possessed remarkable UHF T2 MRI properties (r2 = 152.13 mM-1s-1) and high drug loading capability of 18.4 %. The biodegradation of HMM@T NPs under triple stimulations of pH, GSH, and NIR led to an efficient release of MTO in tumor microenvironment. Our results revealed the potential of a novel UHF MRI-guided multifunctional nanosystem in cancer treatment.

Fluorinated hydrogel nanoparticles with regulable fluorine contents and T2 relaxation times as 19F MRI contrast agents.

Medical imaging contrast agents that are able to provide detailed biological information have attracted increasing attention. Among the new emerging imaging contrast agents, 19F magnetic resonance imaging contrast agents (19F MRI CAs) are extremely promising for their weak background disturbing signal from the body. However, to prepare 19F MRI CAs with a long T2 relaxation time and excellent biocompatibility in a simple and highly effective strategy is still a challenge. Herein, we report a new type of 19F MRI hydrogel nanocontrast agents (19F MRI HNCAs) synthesized by a surfactant-free emulsion polymerization with commercial fluorinated monomers. The T2 relaxation time of 19F MRI HNCA-1 was found to be 25-40 ms, guaranteeing its good imaging ability in vitro. In addition, according to an investigation into the relationship between the fluorine content and 19F MRI signal intensity, the 19F MRI signal intensity was not only determined by the fluorine content in 19F MRI HNCAs but also by the hydration microenvironment around the fluorine atoms. Moreover, 19F MRI HNCAs demonstrated excellent biocompatibility and imaging capability inside cells. The primary exploration demonstrated that 19F MRI HNCAs as a new type of 19F MRI contrast agent hold potential for imaging lesion sites and tracking cells in vivo by 19F MRI technology.

Imitation-mussel fluorescent silicon quantum dots for selective labeling and imaging of bacteria and biofilms.

Selective labeling of distinct bacteria and biofilm is poised for the fundamental understanding of bacterial activities, interactions, and coupled phenomena occurring at the microscale. However, a simple and effective way to achieve selective bacterial labeling is still lacking. Herein, we report a fluorescence probe with core-shell nanostructure that has polydopamine (PDA) coating on the surface of fluorescent silicon quantum dots (SiQDs@PDA). The surface of the SiQDs@PDA can be functionalized by various molecules (2-mercaptoethylamine hydrochloride, PEG, d-alanine, glucose amide) through different strategies (Michael addition, π-π interaction, and ion-ion interaction). Importantly, the d-alanine (D-Ala)- and gluconamide (Glc)-functionalized SiQDs@PDA fluorescence probes are capable of selectively labeling gram-positive and gram-negative bacteria, as well as their biofilms. The excellent performance in universal functionalization and selective labeling and imaging of bacteria and their biofilms demonstrate that SiQDs@PDA are a promising fluorescence tool in microbe research.

Lipid Perfluorohexane Nanoemulsion Hybrid for MRI-Guided High-Intensity Focused Ultrasound Therapy of Tumors.

Magnetic resonance imaging-guided high-intensity focused ultrasound (MRI-guided HIFU) is a non-invasive strategy of diagnosis and treatment that is applicable in tumor ablation. Here, we prepared a multifunctional nanotheranostic agent (SSPN) by loading perfluorohexane (PFH) and superparamagnetic iron oxides (SPIOs) in silica lipid for MRI-guided HIFU ablation of tumors. PFH was introduced to improve the ablation effect of HIFU and the ultrasound (US) contrast performance. Due to its liquid-to-gas transition characteristic, it is sensitive to temperature. SPIOs were used as an MRI contrast agent. Silica lipid was selected because it is a more stable carrier material compared with normal lipid. Previous studies have shown that SSPNs have good biocompatibility, stability, imaging, and therapeutic effects. Therefore, this system is expected to develop an important therapeutic agent for MRI-guided HIFU therapy against tumors.

Degradable Multifunctional Porphyrin-Based Porous Organic Polymer Nanosonosensitizer for Tumor-Specific Sonodynamic, Chemo- and Immunotherapy.

Sonodynamic therapy (SDT) benefiting from its intrinsic merits, such as noninvasiveness and deep tissue penetrability, is receiving increasing considerable attention in reactive oxygen species (ROS)-based tumor treatment. However, current sonosensitizers usually suffer from low tumor lesion accumulation, insufficient ROS generation efficiency under ultrasound, and non-biodegradability, which seriously impede the therapeutic outcomes. Additionally, it is difficult that SDT alone can completely eradicate tumors because of the complex and immunosuppressive tumor microenvironment (TME). Herein, we simultaneously employ sonosensitive porphyrin building blocks and glutathione (GSH)-responsive disulfide bonds to construct a novel degradable multifunctional porphyrin-based hollow porous organic polymer (POP) nanosonosensitizer (H-Pys-HA@M/R), which combine SDT, "on-demand" chemotherapy, and immunotherapy. Taking the unique advantages of POPs with designable structures and high specific surface area, this H-Pys-HA@M/R nanosonosensitizer can achieve tumor target accumulation, GSH-triggered drug release, and low-frequency ultrasound-activating ROS generation with encouraging results. Furthermore, this multifunctional nanosonosensitizer can effectively evoke immunogenic cell death (ICD) response through the combination of SDT and chemotherapy for both primary and distal tumor growth suppression. Meanwhile, H-Pys-HA@M/R exhibits favorable biodegradation and biosafety. Therefore, this study provides a new strategy for reasonably designing and constructing POP-related sonosensitizers combining SDT/chemotherapy/immunotherapy triple treatment modalities to eradicate malignant tumors.