Safe and effective artificial oxygen carriers are the subject of great interest due to the problems of traditional blood transfusion and enormous demand in clinical use. In view of its unique oxygen-transport ability and normal metabolic pathways, hemoglobin is regarded as an ideal oxygen-carrying unit. With advances in nano-biotechnology, hemoglobin assemblies as artificial oxygen carriers achieve great development. Here, recent progress on hemoglobin-based oxygen carriers is highlighted in view of two aspects: acellular hemoglobin-based oxygen carriers and cellular hemoglobin-based oxygen carriers. These novel oxygen carriers exhibit advantages over traditional carriers and will greatly promote research on reliable and feasible oxygen carriers.

Nanostructured drug-carrier systems promise numerous benefits for drug delivery. They can be engineered to precisely control drug-release rates or to target specific sites within the body with a specific amount of therapeutic agent. However, to achieve the best therapeutic effects, the systems should be designed for carrying the optimum amount of a drug to the desired target where it should be released at the optimum rate for a specified time. Despite numerous attempts, fulfilling all of these requirements in a synergistic way remains a huge challenge. The trend in drug delivery is consequently directed toward integrated multifunctional carrier systems, providing selective recognition in combination with sustained or triggered release. Capsules as vesicular systems enable drugs to be confined for controlled release. Furthermore, carriers modified with recognition groups can enhance the capability of encapsulated drug efficacy. Here, recent advances are reviewed regarding designing and preparing assembled capsules with targeting ligands or size controllable for selective recognition in drug delivery.

Objects in all dimensions are subject to translational dynamism and dynamic mutual interactions, and the ability to exert control over these events is one of the keys to the synthesis of functional materials. For the development of materials with truly dynamic functionalities, a paradigm shift from “nanotechnology” to “nanoarchitectonics” is proposed, with the aim of design and preparation of functional materials through dynamic harmonization of atomic-/molecular-level manipulation and control, chemical nanofabrication, self-organization, and field-controlled organization. Here, various examples of dynamic functional materials are presented from the atom/molecular-level to macroscopic dimensions. These systems, including atomic switches, molecular machines, molecular shuttles, motional crystals, metal–organic frameworks, layered assemblies, gels, supramolecular assemblies of biomaterials, DNA origami, hollow silica capsules, and mesoporous materials, are described according to their various dynamic functions, which include short-term plasticity, long-term potentiation, molecular manipulation, switchable catalysis, self-healing properties, supramolecular chirality, morphological control, drug storage and release, light-harvesting, mechanochemical transduction, molecular tuning molecular recognition, hand-operated nanotechnology.

Two-photon activated photodynamic therapy (TPA-PDT) is a recently developed technique that shows a potential for medical application. In contrast to traditional one-photon activated PDT, TPA-PDT can increase the treatment depth and decrease the damage to healthy tissue by using a near-infrared two-photon laser. However, this technique also suffers from the fact that approved photosensitive drugs have a low two-photon absorption cross section. In this study, it is demonstrate that doped polyglycerol mesoporous silica nanoparticles can carry a photosensitizer, Rose bengal, and can be applied in one- and two-photon PDT. TPA dye-doped mesoporous silica nanoparticles have been synthesized using a surfactant-free route, which can be considered a TPA-PDT platform after loading normal photosensitive drugs. The doped TPA dyes in the silica nanoparticles can transfer energy to the loading drugs via an intraparticle fluorescence resonance energy transfer (FRET) mechanism. The fluorescence lifetime and confocal laser scanning microscopy (CLSM) images obtained under different conditions demonstrated a FRET effect through both one- and two-photon activated modes. The results of cytotoxicity experiments proved that this TPA-PDT system could induce cellular apoptosis under one- or two-photon irradiation. This system in principle extends the application range of TPA-PDT.

Advanced multifunctional microcapsules have revealed great potential in biomedical applications owing to their tunable size, shape, surface properties, and stimuli responsiveness. Polysaccharides are one of the most acceptable biomaterials for biomedical applications because of their outstanding virtues such as biocompatibility, biodegradability, and low toxicity. Many efforts have been devoted to investigating novel molecular design and efficient building blocks for polysaccharide-based microcapsules. In this Personal Account, we first summarize the common features of polysaccharides and the main principles of the design and fabrication of polysaccharide-based microcapsules, and further discuss their applications in biomedical areas and perspectives for future research.

Monodispersed diphenylalanine-based nanospheres with excellent biocompatibility are fabricated through a facile covalent reaction-induced assembly. Interestingly, the nanospheres exhibit red autofluorescence. Most importantly, such assembled dipeptide nanospheres can serve as intrinsic photosensitizer to convert O₂ to singlet oxygen (¹O₂). Thus, photodynamic therapy in vitro can be achieved effectively. The versatile strategy could be extended to other biomolecules containing a primary amine group for the fabrication of potential intrinsic photosensitizers.

Small aldehyde molecule are demonstrated to induce cationic diphenylalanine to assemble into monodisperse enzyme-responsive nanocarriers with high biocompatibility and excellent biodegradability. The formation of Schiff base covalent bond and accompanying π–π interaction of aromatic rings are found to be the mainly driving forces for the assembly of the nanocarriers. Interestingly, the nanocarriers show autofluorescence due to the n–π* transitions of C = N bonds, which lends them visually traceable property in living cells. Importantly, the nanocarriers can be taken in by cells and biodegraded in the cells. In addition, doxorubicin is easily loaded into the nanocarriers with high encapsulation amount, and its release can be triggered by tyrisin under physiological conditions. Noticeably, even at a very low drug concentration, the doxorubicin-loaded nanocarriers still exhibit a much higher killing capacity of HeLa cells in vitro, compared to the equivalent-dose free doxorubicin, indicating they have a great potential biomedical application.

Photothermal therapy based on gold nanostructures has been widely investigated as a state-of-the-art noninvasive therapy approach. Because single nanoparticles cannot harvest sufficient energy, self-assemblies of small plasmonic particles into large aggregates are required for enhanced photothermal performance. Self-assembled gold nanorods in lipid bilayer-modified microcapsules are shown to localize at tumor sites, generate vapor bubbles under near-infrared light exposure, and subsequently damage tumor tissues. The polyelectrolyte multilayer enables dense packing of gold nanorods during the assembly process, which leads to the formation of vapor bubbles around the excited capsules. The resulting vapor bubbles achieve a high efficiency of suppressing tumor growth compared to single gold nanorods. In vivo experiments demonstrated the ability of soft-polymer multilayer microcapsules to cross the biological barriers of the body and localize at target tissues.

Photothermal therapy based on gold nanostructures has been widely investigated as a state-of-the-art noninvasive therapy approach. Because single nanoparticles cannot harvest sufficient energy, self-assemblies of small plasmonic particles into large aggregates are required for enhanced photothermal performance. Self-assembled gold nanorods in lipid bilayer-modified microcapsules are shown to localize at tumor sites, generate vapor bubbles under near-infrared light exposure, and subsequently damage tumor tissues. The polyelectrolyte multilayer enables dense packing of gold nanorods during the assembly process, which leads to the formation of vapor bubbles around the excited capsules. The resulting vapor bubbles achieve a high efficiency of suppressing tumor growth compared to single gold nanorods. In vivo experiments demonstrated the ability of soft-polymer multilayer microcapsules to cross the biological barriers of the body and localize at target tissues.

The effect of radioactive UO₂²⁺ on the oxygen-transporting capability of hemoglobin-based oxygen carriers has been investigated in vitro. The hemoglobin (Hb) microspheres fabricated by the porous template covalent layer-by-layer (LbL) assembly were utilized as artificial oxygen carriers and blood substitutes. Magnetic nanoparticles of iron oxide (Fe₃O₄) were loaded in porous CaCO₃ particles for magnetically assisted chemical separation (MACS). Through the adsorption spectrum of magnetic Hb microspheres after adsorbing UO₂²⁺, it was found that UO₂²⁺ was highly loaded in the magnetic Hb microspheres, and it shows that the presence of UO₂²⁺ in vivo destroys the structure and oxygen-transporting capability of Hb microspheres. In view of the high adsorption capacity of UO₂²⁺, the as-assembled magnetic Hb microspheres can be considered as a novel, highly effective adsorbent for removing metal toxins from radiation-contaminated bodies, or from nuclear-power reactor effluent before discharge into the environment.

We demonstrate that an inorganic lanthanide ion (Tb³⁺) or organic dye molecules were encapsulated in situ into diphenylalanine (FF) organogels by a general, simple, and efficient co-assembly process, which generated peptide-based hybrid nanobelts with a range of colored emissions. In the presence of a photosensitizer (salicylic acid), the organogel can serve as an excellent molecular-donor scaffold to investigate FRET to Tb³⁺. More importantly, heat treatment or water induction instigated a morphology transition from nanofibers to nanobelts, after which the participation of guest molecules in the FF assembly was promoted and the stability and photoluminescence emission of the composite organogels were enhanced.

The preparation of 3D hierarchical nanostructures by a simple and versatile strategy of self-assembly of dopamine (DA) and phosphotungstic acid (PTA) is described. The size and morphology of the hierarchical nanostructures could be simply controlled by varying the ratio of the two components, their concentrations, and the pH of the initial Tris-HCl solution. The self-assembly of the flowerlike microspheres has been found to involve a two-stage growth process. Moreover, use of the hierarchical nanostructures as a possible carrier for an anticancer drug in chemotherapy has been explored. The nanostructures showed an intriguing pH-dependent release behavior, making them promising for applications in biomedical science.

Peptide p160-conjugated mesoporous silica nanoparticles (MSN) were fabricated and loaded with photosensitizer hypocrellin B (HB). The results indicate that the nanocomposites have better selectivity for cancer cells and higher cytotoxicity in photodynamic therapy in vitro. The nanocomposites can be used as a novel candidate in photodynamic therapy. This may be a general and promising method to modify nanoparticles to improve their cell affinity.

Doxorubicin, together with the modified polysaccharide (alginate dialdehyde), was used as a wall material to fabricate microcapsules through self-cross-linking by a template method. The microcapsules as-prepared are pH-responsive. Relevant scanning electronic microscopy, atom force microscopy and confocal laser scanning microscopy confirm the morphology of the uniform microcapsules. The spectroscopic results show that the microcapsules are assembled through electrostatic interaction and Schiff's base covalent bonding. Doxorubicin can be released sustainably from the capsules in buffer solution at a lower pH value. The cellular uptake of the microcapsules and drug release induced by acidic microenvironment are time-dependent processes. The cell cytotoxicity experiments in vitro demonstrate that the doxorubicin-based microcapsules have high efficiency to kill the cancer cells.

Bioluminescent microcapsules uploading D-luciferin have been fabricated by using the covalent assembly of firefly luciferase and alginate dialdehyde through a layer-by-layer technique. Such assembled microcapsules can produce visible light in the region of 520–680 nm, which can activate the photosensitizers rose bengal (RB) and hypocrellin B (HB) after adding ATP. The microcapsules uploading photosensitizers (RB or HB) have an obvious property to prevent the proliferation of tumor cells in the dark. The assembled bioluminescent microcapsules can be potentially used as photon donors for bioimaging, ATP detection, and photodynamic therapy.

This study describes a facile breath-figure method for the preparation of honeycomb-like porous TiO₂ films with an organometallic small-molecule precursor. Multiple characterization techniques have been used to investigate the porous films and a mechanism for the formation process of porous TiO₂ films through the breath-figure method is proposed. The pore size of the TiO₂ films could be modulated by varying the experimental parameters, such as the concentration of titanium n-butoxide (TBT) solution, the content of cosolvent, and the air flow rate. In vitro cell-culture experiments indicate that NIH 3T3 fibroblast cells seeded on the honeycomb-like porous TiO₂ films show good adhesion, spreading, and proliferation behaviors, which suggests that honeycomb-like porous TiO₂ films are an attractive biomaterial for surface modification of titanium and its alloys implants in tissue engineering to enhance their biocompatibility and bioactivity.

A reactive template method was used to fabricate alginate-based hydrogel microcapsules. The uniform and well-dispersed hydrogel capsules have a high drug loading capacity. After they are coated by a folate-linked lipid mixture on the surface, the capsules possess higher cell uptake efficiency by the molecule recognition between folate and the folate-receptor overexpressed by the cancer cells. Moreover, in this bioconjugate, the lipid could remarkably reduce the release rate of hydrophilic doxorubicin from the hydrogel microcapsules and encapsulate the hydrophobic photosensitizer hypocrellin B. The biointerfaced capsules could be used as drug carriers for combined treatment against cancer cell proliferation in vitro; this was much more effective than chemotherapy or photodynamic therapy alone.

In this paper, we propose a “casting” strategy to prepare intrinsically fluorescent, uniform and porous gelatin microgels with multi-responsiveness. Gelatin microgels with tunable size were obtained by copying the structure of a porous CaCO₃ template. The diameter of the gelatin microgels was sensitive to salt concentration and pH. Doxorubicin and Rhodamine B as model drugs were loaded into the microgels via electrostatic interaction and release of the payload was triggered by changing the salt concentration and pH, respectively. Cell experiments demonstrated that the gelatin microgels had an excellent biocompatibility and biodegradability. The merits of gelatin microgels such as tunable size, biocompatibility, and stimulus responsive upload and release of positively charged small molecules will permit the microgels as excellent carriers for drug delivery. The whole manufacturing process is furthermore environmental-friendly involving no organic solvents and surfactants.

Hemoglobin-based capsules for use as blood substitutes are successfully fabricated by covalent layer-by-layer assembly. Dialdehyde heparin (DHP) is used both as one of the wall components and a cross-linker without employing other extraneous or toxic crosslinking agents. The biocompatibility of (Hb/DHP)₆ microcapsules is evaluated through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay and cell experiments. The hemocompatibility of (Hb/DHP)₆ microcapsules is characterized in terms of prothrombin time, thrombin time, activated partial thromboplastin time, and hemolysis rate. The oxygen-carrying capacity of the microcapsules is demonstrated by converting the deoxy-Hb state of the microcapsules into the oxy-Hb state. All these results demonstrate that the hemoglobin-based microcapsules exhibit oxygen-carrying capacity as well as biocompatibility and hemocompatility, indicating that the as-prepared capsules have great potential to function as blood substitutes.

Autofluorescent microcapsules were assembled by covalent cross-linking of polysaccharide alginate dialdehyde (ADA) derivative and cystamine dihydrochloride (CM) through a layer-by-layer (LBL) technique. The formulated Schiff base and disulfide bonds render capsules with pH- and redox-responsive properties for pinpointed intracellular delivery based on the physiological difference between intracellular and extracellular environments. This simple and versatile method could be extended to other polysaccharide derivatives for the fabrication of autofluorescent nano- and micromaterials with dual stimuli response for biomedical applications.

Heparin (HEP) and periodate-oxidized heparin (O-HEP) nanotubes were prepared by combining the template method with a layer-by-layer (LbL) technique. The tubular structure was obtained and characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), and confocal laser scanning microscopy (CLSM). O-HEP is one of the HEP derivatives that contains anticoagulant activity and preserves its ability for other effects. Chitosan (CHI) and O-HEP have been used to fabricate nanotubes by covalent cross-linking Schiff base reactions. It is demonstrated that the obtained nanotubes have the significant feature of autofluorescence without the addition of any fluorescent dyes and they retain their anticoagulation activity. Compared with O-HEP/CHI nanotubes, HEP/CHI nanotubes show high anticoagulation activity and do not have autofluorescence. Furthermore, this method could be extended to other copolysaccharide derivatives for the preparation of autofluorescent nanomaterials.

The self-assembly of molecules into desired architectures is currently a challenging subject for the development of supramolecular chemistry. Here we present a facile “breath figure” assembly process through the use of the self-assembled peptide building block diphenylalanine (L-Phe-L-Phe, FF). Macroporous honeycomb scaffolds were fabricated, and average pore size could be regulated, from (1.00±0.18) μm to (2.12±0.47) μm, through the use of different air speeds. It is indicated that the honeycomb formation is humidity-, solvent-, concentration-, and substrate-dependent. Moreover, water molecules introduced from “breath figure” intervene in the formation of hydrogen bonds during FF molecular self-assembly, which results in a hydrogen bond configuration transition from antiparallel β sheet to parallel β sheet. Meanwhile, as a result of the higher polarity of water molecules, the FF molecular array is transformed from laminar stacking into a hexagonal structure. These findings not only elucidate the FF molecule self-assembly process, but also strongly support the mechanism of breath figure array formation. Finally, human embryo skin fibroblast (ESF) culture experiments suggest that FF honeycomb scaffolds are an attractive biomaterial for growth of adherent cells with great potential applications in tissue engineering.

The design and fabrication of various nanostructures with predefined geometry and composition is a big challenge of nanotechnology. Here we demonstrate an Au nanoflake film replicated from a self-assembled, well-ordered, dipeptide flower-like hierarchical architecture. Such morphology can give rise to useful and remarkable surface-enhanced Raman spectroscopy (SERS) properties. We obtained these nanostructures by using a scaffold of flake-built spherical dipeptide aggregations. Gold nanoparticles were sputtered on the surface of as-assembled dipeptide by an etching system. After removing the dipeptide templates by ethanol, a metal crust was left with a morphology similar to that of the dipeptide hierarchical structure. The different steps within the process were monitored by using electron microscopy, energy-dispersive spectrum (EDS) analysis and atomic force microscopy (AFM). Cyclic voltammetry and Raman spectra were employed to prove the SERS effect of the obtained Au substrates. The enhancement factor is estimated to be about 10⁴ for 4-mercaptobenzoic acid (4-MBA) molecules on the Au nanoflake surfaces.

Organogels that are self-assembled from simple peptide molecules are an interesting class of nano- and mesoscale soft matter with simplicity and functionality. Investigating the precise roles of the organic solvents and their effects on stabilization of the formed organogel is an important topic for the development of low-molecular-weight gelators. We report the structural transition of an organogel self-assembled from a single dipeptide building block, diphenylalanine (L-Phe-L-Phe, FF), in toluene into a flower-like microcrystal merely by introducing ethanol as a co-solvent; this provides deeper insights into the phase transition between mesostable gels and thermodynamically stable microcrystals. Multiple characterization techniques were used to reveal the transitions. The results indicate that there are different molecular-packing modes formed in the gels and in the microcrystals. Further studies show that the co-solvent, ethanol, which has a higher polarity than toluene, might be involved in the formation of hydrogen bonds during molecular self-assembly of the dipeptide in mixed solvents, thus leading to the transition of organogels into microcrystals. The structural transformation modulated by the co-solvent might have a potential implication in controllable molecular self-assembly.

The fabrication of polyelectrolyte multilayer capsules with controllable submicron-sized subdomains and the in situ synthesis of silver nanoparticles are reported. Because poly(acrylic acid) (PAA) is released from the shell of the capsules in the dissolution process of sacrificial cores, the remaining poly(4-vinylpyridine) (PVP) forms subdomains of spheres with controllable sizes, which can be tuned by the number of PVP/PAA bilayers. This creates capsules with special surface morphology and enables the in situ synthesis of Ag nanoparticles within the PVP subdomains on the shell of capsules. In addition, the in-situ formed Ag nanoparticles can be mostly released from PVP subdomains of capsules in pH 2.0 solution, whereas they are stable in neutral solution. These specially designed capsules containing Ag nanoparticles can be used as antimicrobial materials and potentially benefit remote drug release by laser activation.

Peptide-based self-assembling systems are increasingly attractive because of their wide range of applications in different fields. Peptide nanostructures are flexible with changes in the ambient conditions. Herein, a reversible shape transition between self-assembled dipeptide nanotubes (DPNTs) and vesicle-like structures is observed upon a change in the peptide concentration. SEM, TEM, AFM, and CD spectroscopy were used to follow this transition process. We show that dilution of a peptide-nanotube dispersion solution results in the formation of vesicle-like structures, which can then be reassembled into the nanotubes by concentrating the solution. A theoretical model describing this shape-transition phenomenon is presented to propose ways to engineer assembling molecules in order to devise other systems in which the morphology can be tuned on demand.