The mimicking of biological supramolecular interactions and their mutual transitions to fabricate intelligent artificial systems has been of increasing interest. Herein, we report the fabrication of supramolecular micellar nanoparticles consisting of quaternized poly(ethylene oxide)-b-poly(2-dimethylaminoethyl methacrylate) (PEO-b-PQDMA) and tetrakis(4-carboxylmethoxyphenyl)ethene (TPE-4COOH), which was capable of reversible transition between polyion complexes (PIC) and hydrogen bonding complexes (HBC) with tunable aggregation-induced emission (AIE) mediated by solution pH. At pH 8, TPE-4COOH chromophores can be directly dissolved in aqueous milieu without evident fluorescence emission. However, upon mixing with PEO-b-PQDMA, polyion complexes were formed by taking advantage of electrostatic interaction between carboxylate anions and quaternary ammonium cations and the most compact PIC micelles were achieved at the isoelectric point (i.e., [QDMA+]/[COO–] = 1), as confirmed by dynamic light scattering (DLS) measurement. Simultaneously, fluorescence spectroscopy revealed an evident emission turn-on and the maximum fluorescence intensity was observed near the isoelectric point due to the restriction of intramolecular rotation of TPE moieties within the PIC cores. The kinetic study supported a micelle fusion/fission mechanism on the formation of PIC micelles at varying charge ratios, exhibiting a quick time constant (τ1) relating to the formation of quasi-equilibrium micelles and a slow time constant (τ2) corresponding to the formation of final equilibrium micelles. Upon deceasing the pH of PIC micelles from 8 to 2 at the [QDMA+]/[COO–] molar ratio of 1, TPE-4COOH chromophores became gradually protonated and hydrophobic. The size of micellar nanoparticles underwent a remarkable decrease, whereas the fluorescence intensity exhibited a further increase by approximately 7.35-fold, presumably because of the formation of HBC micelles comprising cationic PQDMA coronas and PEO/TPE-4COOH hydrogen-bonded cores, an inverted micellar structures compared to initial PIC micelles. Moreover, the pH-mediated schizophrenic micellar transition from PIC to HBC with tunable AIE characteristic was reversible.Keywords: aggregation-induced emission; hydrogen bonding complex; pH-responsive; polyion complex; schizophrenic micelle; supramolecular interaction

Supramolecular vesicles, also referred to as polymersomes, self-assembled from amphiphilic polymers capable of synchronically loading with both hydrophilic and hydrophobic payloads have shown promising potential in drug delivery application. Herein, we report the fabrication of pH-responsive polymersomes via supramolecular self-assembly of amphiphilic diblock copolymers, poly(ethylene oxide)-b-poly(2-((((5-methyl-2-(2,4,6-trimethoxyphenyl)-1,3-dioxan-5-yl)methoxy)carbonyl)amino)ethyl methacrylate) (PEO-b-PTTAMA), which were synthesized via reversible addition–fragmentation chain transfer (RAFT) polymerization of a pH-responsive monomer (i.e., TTAMA) using a PEO-based macroRAFT agent. The resultant amphiphilic diblock copolymer then self-assembled into vesicles consisting of hydrophilic PEO coronas and pH-responsive hydrophobic bilayers, as confirmed by TEM and DLS measurements. The polymersomes containing cyclic benzylidene acetals in the hydrophobic bilayers were relatively stable under neutral pH, whereas they underwent hydrolysis with the liberation of hydrophobic 2,4,6-trimethoxybenzaldehyde and the simultaneous generation of hydrophilic diol moieties upon exposure to acidic pH milieu, which could be monitored by UV/vis spectroscopy, SEM, and TEM observations. By loading hydrophobic model drug (Nile red) as well as hydrophilic chemotherapeutic drug (doxorubicin hydrochloride, DOX·HCl) into the bilayer and aqueous interior of the polymersomes, the subsequent release of Nile red and DOX·HCl payloads was remarkably regulated by the solution pH values, and a lower pH value led to a faster drug release profile. In vitro experiment, observed by a confocal laser scanning microscope (CLSM), revealed that the pH-responsive polymersomes were easily taken up by HeLa cells and were primarily located in the acidic organelles after internalization, where the pH-responsive cyclic acetal moieties were hydrolyzed and the embedded payloads were therefore released, allowing for on-demand release of the encapsulants mediated by intracellular pH. In addition to small molecule chemotherapeutic drugs, biomacromolecules (alkaline phosphatase, ALP) can also be encapsulated into the aqueous lumen of the polymersomes. Significantly, the pH-triggered degradation of polymersomes could also regulate the release of encapsulated ALP, as confirmed by ALP-activated fluorogenic reaction.

We report on the synthesis of star copolymers possessing dual functions of gene delivery vectors and magnetic resonance (MR) imaging contrast enhancement. Starting from asymmetrically functionalized β-cyclodextrin (β-CD) comprising 7 azide moieties and 14 α-bromopropionate functionalities at the upper and lower rim of a rigid toroidal β-CD core, (DOTA-Gd)7-CD-(PDMA)14 star copolymers were synthesized via atom transfer radical polymerization (ATRP) of N,N-dimethylaminoethyl methacrylate (DMA) and subsequent click reaction with an alkynyl-functionalized gadolinium (Gd3+) complex, DOTA-Gd, where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. The obtained Janus-type star copolymers, (DOTA-Gd)7-CD-(PDMA)14, could completely complex with anionic plasmid DNA (pDNA) via electrostatic interactions at N/P ratios equal to or higher than 2 and exhibit optimal in vitro transfection efficiency at an N/P ratio of 8. In addition, in vitro MR imaging experiments demonstrated considerably enhanced T1 relaxivity (r1 ∼ 10.9 s−1 mM−1) for the star copolymer compared to that of commercially available small molecular MR imaging contrast agents (2.4–3.2 s−1 mM−1). The star-type topology of asymmetrically functionalized β-CD based copolymers in combination with the integrated design of diagnostic and therapeutic functions augurs well for their potential applications in the field of image-guided gene therapy.

Solution self-assembly of block copolymers (BCPs) typically generates spheres, rods, and vesicles. The reproducible bottom-up fabrication of stable planar nanostructures remains elusive due to their tendency to bend into closed bilayers. This morphological vacancy renders the study of shape effects on BCP nanocarrier-cell interactions incomplete. Furthermore, the fabrication of single BCP assemblies with built-in drug delivery functions and geometry-optimized performance remains a major challenge. We demonstrate that PEG-b-PCPTM polyprodrug amphiphiles, where PEG is poly(ethylene glycol) and PCPTM is polymerized block of reduction-cleavable camptothecin (CPT) prodrug monomer, with >50 wt % CPT loading content can self-assemble into four types of uniform nanostructures including spheres, large compound vesicles, smooth disks, and unprecedented staggered lamellae with spiked periphery. Staggered lamellae outperform the other three nanostructure types, exhibiting extended blood circulation duration, the fastest cellular uptake, and unique internalization pathways. We also explore shape-modulated CPT release kinetics, nanostructure degradation, and in vitro cytotoxicities. The controlled hierarchical organization of polyprodrug amphiphiles and shape-tunable biological performance opens up new horizons for exploring next-generation BCP-based drug delivery systems with improved efficacy.