Direct C-H Arylation Derived Ternary D-A Conjugated Polymers: Effects of Monomer Geometries, D/A Ratios, and Alkyl Side Chains on Photocatalytic Hydrogen Production and Pollutant Degradation.

Donor-acceptor (D-A) conjugated polymer (CP) featuring high charge mobility and widely tunable energy bands have shown promising prospects in photocatalysis. In this work, a library of ternary D-A CPs (22 polymers) based on benzothiadiazole, bithiophene, and fluorene derivatives (i.e., fluorene [Fl], 9,9-dihexylfluorene [HF], and 9,9'-spirobifluorene [SF]) with and without alkyl side chains, and with 3D geometry are designed and synthesized via atom-economical direct C-H arylation polymerization to explore the synergetic effects of stereochemistry, D/A ratio, and alkyl chains on the properties and photocatalytic performances, which reveal that 1) the cross-shaped 3D spirobifluorene (SF) building block shows the highest hydrogen evolution rates (HER) owing to the sufficient photocatalytic active sites exposed, 2) the alkyl-free linear polymer (FlBtBT0.05 ) exhibit the highest photocatalytic pollutant degradation performance owing to its superior charge separation, and 3) the alkyl side chains are redundances that will exert detrimental effects on the aqueous photocatalysis owing to their insulating and hydrophobic property. The structure-property-performance correlation results obtained will provide a desirable guideline for the rational design of CP-based photocatalysts.

Precision Sequence-Defined Polymers: From Sequencing to Biological Functions.

Precise sequence-defined polymers (SDPs) with uniform chain-to-chain structure including chain length, unit sequence, and end functionalities represent the pinnacle of sophistication in the realm of polymer science. For example, the absolute control over the unit sequence of SDPs allows for the bottom-up design of polymers with hierarchical microstructures and functions. Accompanied with the development of synthetic techniques towards precision SDPs, the decoding of SDP sequences and construction of advanced functions irreplaceable by other synthetic materials is of central importance. In this Minireview, we focus on recent advances in SDP sequencing techniques including tandem mass spectrometry (MS), chemically assisted primary MS, as well as other non-destructive sequencing methods such as nuclear magnetic resonance (NMR) spectroscopy, circular dichroism (CD), and nanopore sequencing. Additionally, we delve into the promising prospects of SDP functions in the area of cutting-edge biological research. Topics of exploration include gene delivery systems, the development of hybrid materials combining SDPs and nucleic acids, protein recognition and regulation, as well as the interplay between chirality and biological functions. A brief outlook towards the future directions of SDPs is also presented.

Self-Amplified Cascade Degradation and Oxidative Stress Via Rational pH Regulation of Oxidation-Responsive Poly(ferrocene) Aggregates.

Precise activation of polymer nanoparticles at lesion sites is crucial to achieve favorable therapeutic efficacy. However, conventional endogenous stimuli-responsive polymer nanoparticles probably suffer from few triggers to stimulate the polymer degradation and subsequent functions. Here, we describe oxidation-responsive poly(ferrocene) amphiphiles containing phenylboronic acid ester and ferrocene as the repeating backbone units. Upon triggering by hydrogen peroxide inside the tumor cells, the phenylboronic acid ester bonds are broken and poly(ferrocene) units are degraded to afford free ferrocene and noticeable hydroxide ions. The released hydroxide ions can immediately improve the pH value within the poly(ferrocene) aggregates, and the degradation rate of the phenylboronic acid ester backbone is further promoted by the upregulated pH; thereupon, the accelerated degradation can release much more additional hydroxide ions to improve the pH, thus achieving a positive self-amplified cascade degradation of poly(ferrocene) aggregates accompanied by oxidative stress boosting and efficient cargo release. Specifically, the poly(ferrocene) aggregates can be degraded up to ∼90% within 12 h when triggered by H2O2, while ferrocene-free control nanoparticles are degraded by only 30% within 12 days. In addition, the maleimide moieties tethered in the hydrophilic corona can capture blood albumin to form an albumin-rich protein corona and significantly improve favorable tumor accumulation. The current oxidation-responsive poly(ferrocene) amphiphiles can efficiently inhibit tumors in vitro and in vivo. This work provides a proof-of-concept paradigm for self-amplified polymer degradation and concurrent oxidative stress, which is promising in actively regulated precision medicine.

Overcoming the Dilemma of Permeability and Stability of Polymersomes through Traceless Cross-Linking.

In nature, cells are highly compartmentalized into many organelles that are well separated from the rest of the cellular space by unique membrane structures, which are of crucial importance to allow cells to perform various physiological functions in such a small and crowded space. Learning from the ubiquitous membrane structures of cells and organelles has continuously inspired the development of artificial self-assembled nanostructures, with lipid vesicles (liposomes) and polymer vesicles (polymersomes) being the most representative examples. Similar to the membrane-bound structures of cells and organelles, both liposomes and polymersomes contain an aqueous interior enclosed by a bilayer membrane. Therefore, liposomes and polymersomes have been extensively investigated to mimic the fundamental structures and functions of living cells. For example, liposomes and polymersomes have been successfully engineered as nanocarriers, smart nanoreactors, artificial organelles, and so on. Notably, living cells can exchange both energy and materials with surrounding environments, benefiting from the selective permeability of lipid membranes. The permselectivity of cell membranes is thus an essential attribute of living organisms. Compared to liposomes, polymersomes have increased structural stability but low membrane permeability. Indeed, polymersomes are almost impermeable to small molecules, ions, and even water molecules. To improve the permeability of polymersomes, much effort has been devoted to the incorporation of channel proteins, the coassembly of oppositely charged block copolymers (BCPs), the development of stimuli-responsive BCPs, and so on. Despite great achievements, these approaches generally lead to decreased stability of polymersomes and, sometimes, polymersome disintegration. In this Account, we discuss our recent efforts to reconcile the stability and permeability of polymersomes via a traceless cross-linking approach. Although cross-linking reactions within bilayer membranes generally lead to decreased permeability, the traceless cross-linking approach can concurrently improve the stability and permeability of polymersomes. Specifically, stimuli-responsive polymersomes undergo either covalent cross-linking or noncovalent cross-linking reactions under specific stimuli to increase bilayer stability, while the cross-linking processes can concurrently permeabilize polymersome bilayers through cross-linking-driven hydrophobic-to-hydrophilic transitions. Notably, unlike conventional cross-linking processes requiring additional cross-linkers, the traceless cross-linking process does not involve extra cross-linking agents but takes full advantage of the in situ generated active moieties. By taking advantage of the simultaneous modulation of the stability and permeability of polymersomes via traceless cross-linking, these polymersomes can be further engineered as smart nanocarriers and nanoreactors. The robustness and generality of this approach have been validated by both extracellular and intracellular stimuli such as light irradiation, glutathione, and hydrogen peroxide. Moreover, many functional groups such as fluorescent dyes and contrast agents can be integrated into this versatile platform as well, enabling the construction of theranostic nanovectors capable of responding to pathological microenvironments. This Account provides a new approach to regulating the permeability of polymersomes while maintaining their structural stability.

Effect of Controlling Thiophene Rings on D-A Polymer Photocatalysts Accessed via Direct Arylation for Hydrogen Production.

Conjugated polymer photocatalysts for hydrogen production have the advantages of an adjustable structure, strong response in the visible light region, adjustable energy levels, and easy functionalization. Using an atom- and step-economic direct C-H arylation method, dibromocyanostilbene was polymerized with thiophene, dithiophene, terthiophene, and fused thienothiophene and dithienothiophene, respectively, to produce donor-acceptor (D-A)-type linear conjugated polymers containing different thiophene derivatives with different conjugation lengths. Among them, the D-A polymer photocatalyst constructed from dithienothiophene could significantly broaden the spectral response, with a hydrogen evolution rate up to 12.15 mmol h-1 g-1. The results showed that the increase in the number of fused rings on thiophene building blocks was beneficial to the photocatalytic hydrogen production of cyanostyrylphene-based linear polymers. For the unfused dithiophene and terthiophene, the increase in the number of thiophene rings enabled more rotation freedom between the thiophene rings and reduced the intrinsic charge mobility, resulting in lower hydrogen production performance accordingly. This study provides a suitable process for the design of electron donors for D-A polymer photocatalysts.

Self-Immolative Amphiphilic Poly(ferrocenes) for Synergistic Amplification of Oxidative Stress in Tumor Therapy.

Amphiphilic self-immolative polymers (SIPs) can achieve complete degradation solely through one triggerable event, which potentially optimize the blood clearance and uncontrollable/inert degradability for therapeutic nanoparticles. Herein, we report self-immolative amphiphilic poly(ferrocenes), BPnbs -Fc, composed by self-immolative backbone and aminoferrocene (AFc) side chains as well as end-capping poly(ethylene glycol) monomethyl ether. Upon triggering by tumor acidic milieu, the BPnbs -Fc nanoparticles readily degrade to release azaquinone methide (AQM) moieties, which can rapidly deplete intracellular glutathione (GSH) to cascade release AFc. Furthermore, both AFc and its product Fe2+ can catalyze intracellular hydrogen peroxide (H2 O2 ) into highly reactive hydroxyl radicals (⋅OH), thus amplifying the oxidative stress of tumor cells. Rational synergy of GSH depletion and ⋅OH burst can efficiently inhibit tumor growth by the SIPs in vitro and in vivo. This work provides an elegant design to adopt innate tumor milieu-triggerable SIPs degradation to boost cellular oxidative stress, which is a promising candidate for precision medicine.

Dendritic Quaternary-Encoded Oligourethanes for Data Encryption.

The use of sequence-defined digital polymers for data storage and encryption has received increasing attention due to their precision structures similar to natural biomacromolecules (e.g., DNA) but increased stability. However, the rapid development of sequencing techniques raises the concern of information leakage. Herein, dendritic quaternary-encoded oligourethanes bearing a photoresponsive trigger, self-immolative backbones, and a mass spectrometry tag of PEG dendron have been developed for data encryption. Although the sequence information in linear analogs can be readily deciphered by mass spectrometry, sequencing of dendritic oligourethanes cannot be achieved by either primary MS or tandem MS/MS owing to the unique spatial conformation. Intriguingly, the fragmentation pathways of a quaternary dendrimer under MS/MS conditions can be converted to 2772-bit 2D matrices with ≈1.98×1087 permutations, serving as high-strength encryption keys for highly reliable data encryption.

Fluorinated Copolypeptide-Stabilized Microbubbles with Maleimide-Decorated Surfaces as Long-Term Ultrasound Contrast Agents.

Gas-filled microbubbles (MBs) have been clinically used as ultrasound (US) contrast agents for disease diagnosis and treatment. However, it remains a great challenge to resolve the dilemma of stability and contrast enhancement of MBs. Herein, amphiphilic copolypeptides bearing fluorinated blocks are synthesized to stabilize perfluorocarbon (PFC)-filled MBs, exhibiting unique stability under both long-term storage and US imaging conditions. The fluorinated inner layer reduces the internal Laplace pressure and greatly improves the stability of MBs, which can be further reinforced by crosslinking of the dipropargyl-containing middle blocks. To overcome the suppressed nonlinear oscillation of polymer shells, maleimide groups are introduced onto the surface of MBs, enabling in situ reaction with plasma proteins to enhance second harmonic signals without compromising the stability of MBs, conferring better US imaging performance than that of SonoVueTM MBs.

Disulfide-Based Self-Immolative Linkers and Functional Bioconjugates for Biological Applications.

It is of vital importance to reversibly mask and selectively activate bioactive agents for advanced therapeutic and diagnostic purposes, aiming to efficiently suppress background interferences and attenuate systemic toxicity. This strategy has been involved in diverse applications spanning from chemical/biological sensors and diagnostics to drug delivery nanocarriers. Among these, redox-responsive disulfide linkages have been extensively utilized by taking advantage of extracellular and intracellular glutathione (GSH) gradients. However, direct conjugation of cleavable triggers to bioactive agents through disulfide bonds suffers from bulky steric hindrance and limited choice of trigger-drug combinations. Fortunately, the emergence of disulfide self-immolative linkers (DSILs) provides a general and robust strategy to not only mask various bioactive agents through the formation of dynamic disulfide linkages but also make it possible to be selectively activated upon disulfide cleavage in the reductive cytoplasmic milieu. In this review, recent developments in DSILs are focused with special attention on emerging chemical design strategies and functional applications in the biomedical field.

Novel Diketopyrrolopyrrole-Based π-Conjugated Molecules Synthesized Via One-Pot Direct Arylation Reaction.

Diketopyrrolopyrrole (DPP) is an important type of π-conjugated building block for high-performance organic electronic materials. DPP-based conjugated materials are usually synthesized via Suzuki, Stille, or Negishi cross-coupling reactions, which require organometallic precursors. In this paper, a series of novel phenyl-cored DPP molecules, including five meta-phenyl-cored molecules and four para-phenyl-cored molecules, have been synthesized in moderate to good yields, in a facile manner, through the Pd-catalyzed direct arylation of C-H bonds, and their optoelectrical properties have been investigated in detail. All new molecules have been fully characterized by NMR, MALDI-TOF MS, elemental analysis, UV-visible spectroscopy, and cyclic voltammetry. This synthetic strategy has evident advantages of atom- and step-economy and low cost, compared with traditional cross-coupling reactions.

Photo- and Reduction-Responsive Polymersomes for Programmed Release of Small and Macromolecular Payloads.

We report on the preparation of photo- and reduction-responsive diblock copolymers through reversible addition-fragmentation chain transfer (RAFT) polymerization of a coumarin-based disulfide-containing monomer (i.e., CSSMA) using a poly(ethylene oxide) (PEO)-based macroRAFT agent. The resulting amphiphilic PEO- b-PCSSMA copolymers self-assembled into polymersomes with hydrophilic PEO shielding coronas and hydrophobic bilayer membranes. Upon irradiating the polymersomes with visible light (e.g., 430 nm), the coumarin moieties within the bilayer membranes were cleaved with the generation of primary amine groups, which spontaneously underwent inter/intrachain amidation reactions with the ester moieties, thereby tracelessly cross-linking and permeating the bilayer membranes. Notably, this process only gave rise to the release of small molecule payloads (e.g., doxorubicin hydrochloride, DOX) while large molecule encapsulants (e.g., Texas red-labeled dextran, TR-dextran) were retained within the cross-linked polymersomes due to the preservation of the integrity of the vesicular nanostructures. However, cross-linked polymersomes undergo further structural disintegration upon incubation with glutathione (GSH) due to the scission of disulfide linkages, resulting in the release of macromolecular payloads. Thus, dual-stimuli responsive polymersomes with tracelessly cross-linkable characteristics enable sequential release of payloads with spatiotemporal precision, which could be of promising applications in synergistic loading and programmed release of therapeutics.

Fabrication of pH- and Thermoresponsive Three-Layered Micelles via Host-Guest Interactions.

Well-defined ß-cyclodextrin (ß-CD)-terminated double hydrophilic diblock copolymers (DHBCs), ß-CD- poly(di(ethylene glycol) methyl ether methacrylate) (PMEO2 MA)-b-poly(2-(diethylamino)ethyl methacrylate) (PDEA) (BP1) and ß-CD-PDEA-b-PMEO2 MA (BP2), are synthesized via sequential atom transfer radical polymerizations of di(ethylene glycol) methyl ether methacrylate and 2-(diethylamino)ethyl methacrylate using alkynyl-functionalized initiator, followed by click reactions with an excess of mono-azido-substituted ß-cyclodextrin (ß-CD-N3 ). The micellization behavior of these as-prepared DHBCs in aqueous solutions suffers from insufficient colloidal stabilities at basic pH and high temperatures (e.g., pH 9 and 45 °C), resulting in the formation of macroscopic precipitations. However, the stabilities of colloidal nanoparticles can be remarkably enhanced as a result of the convenient formation of three-layered micelles by taking advantage of host-guest interactions of BP1/BP2 and Ad-terminated poly(ethylene glycol). The pH- and thermoresponsive three-layered micelles with enhanced stability may augur promising applications in targeted drug delivery and controlled intelligent release.

Reactive Oxygen, Nitrogen, and Sulfur Species (RONSS)-Responsive Polymersomes for Triggered Drug Release.

Reactive oxygen, nitrogen, and sulfur species (RONSS) are cross-reacting and involved in a myriad of physiological and pathological processes. Similar to acidic pH, overexpressed enzymes, and other specific stimuli found in pathological microenvironments, RONSS are recognized as a category of emerging triggering events and have been employed to design activatable theranostic nanomaterials. In this regard, a plethora of RONSS-responsive nanovectors including polymeric micelles and vesicles (also referred to as polymersomes) are constructed. In comparison with micelles, polymersomes comprising aqueous interiors enclosed by hydrophobic membranes show intriguing applications in synergistic delivery of both hydrophobic and hydrophilic drugs, nanoreactors, and artificial organelles. This feature article focuses on the recent developments in the fabrication of RONSS-responsive polymersomes and their potential biomedical applications in terms of triggered drug delivery.

Doubly Caged Linker for AND-Type Fluorogenic Construction of Protein/Antibody Bioconjugates and In Situ Quantification.

In situ quantification of the conjugation efficiency of azide-terminated synthetic polymers/imaging probes and thiol-functionalized antibodies/proteins/peptides was enabled by a doubly caged profluorescent and heterodifunctional core molecule C1 as a self-sorting bridging unit. Orthogonal dual "click" coupling of C1 with azide- and thiol-functionalized precursors led to highly fluorescent bioconjugates, whereas single-click products remained essentially nonfluorescent. Integration with FRET processes was also possible. For the construction of antibody-probe conjugates from an anti-carcinoembryonic antigen and a quinone-caged profluorescent naphthalimide derivative, the dual "click" coupling process with C1 was monitored on the basis of the emission turn-on of C1, whereas prominent changes in FRET ratios occurred for antibody-imaging-probe conjugates when specifically triggered by quinone oxidoreductase (NQO1), which is overexpressed in various types of cancer cells.

Engineering Intracellular Delivery Nanocarriers and Nanoreactors from Oxidation-Responsive Polymersomes via Synchronized Bilayer Cross-Linking and Permeabilizing Inside Live Cells.

Reactive oxygen species (ROS) and oxidative stress are implicated in various physiological and pathological processes, and this feature provides a vital biochemical basis for designing novel therapeutic and diagnostic nanomedicines. Among them, oxidation-responsive micelles and vesicles (polymersomes) of amphiphilic block copolymers have been extensively explored; however, in previous works, oxidation by ROS including H2O2 exclusively leads to microstructural destruction of polymeric assemblies. For oxidation-responsive polymersomes, fast release of encapsulated hydrophilic drugs and bioactive macromolecules will occur upon microstructural disintegration. Under certain application circumstances, this does not meet design requirements for sustained-release drug nanocarriers and long-acting in vivo nanoreactors. Also note that conventional polymersomes possess thick hydrophobic bilayers and compromised membrane permeability, rendering them as ineffective nanocarriers and nanoreactors. We herein report the fabrication of oxidation-responsive multifunctional polymersomes exhibiting intracellular milieu-triggered vesicle bilayer cross-linking, permeability switching, and enhanced imaging/drug release features. Mitochondria-targeted H2O2 reactive polymersomes were obtained through the self-assembly of amphiphilic block copolymers containing arylboronate ester-capped self-immolative side linkages in the hydrophobic block, followed by surface functionalization with targeting peptides. Upon cellular uptake, intracellular H2O2 triggers cascade decaging reactions and generates primary amine moieties; prominent amidation reaction then occurs within hydrophobic bilayer membranes, resulting in concurrent cross-linking and hydrophobic-to-hydrophilic transition of polymersome bilayers inside live cells. This process was further utilized to achieve integrated functions such as sustained drug release, (combination) chemotherapy monitored by fluorescence and magnetic resonance (MR) imaging turn-on, and to construct intracellular fluorogenic nanoreactors for cytosolic thiol-containing bioactive molecules.

Enzyme-Responsive Polymeric Vesicles for Bacterial-Strain-Selective Delivery of Antimicrobial Agents.

Antimicrobial resistance poses serious public health concerns and antibiotic misuse/abuse further complicates the situation; thus, it remains a considerable challenge to optimize/improve the usage of currently available drugs. We report a general strategy to construct a bacterial strain-selective delivery system for antibiotics based on responsive polymeric vesicles. In response to enzymes including penicillin G amidase (PGA) and ß-lactamase (Bla), which are closely associated with drug-resistant bacterial strains, antibiotic-loaded polymeric vesicles undergo self-immolative structural rearrangement and morphological transitions, leading to sustained release of antibiotics. Enhanced stability, reduced side effects, and bacterial strain-selective drug release were achieved. Considering that Bla is the main cause of bacterial resistance to ß-lactam antibiotic drugs, as a further validation, we demonstrate methicillin-resistant S. aureus (MRSA)-triggered release of antibiotics from Bla-degradable polymeric vesicles, in vitro inhibition of MRSA growth, and enhanced wound healing in an in vivo murine model.

Cell-penetrating hyperbranched polyprodrug amphiphiles for synergistic reductive milieu-triggered drug release and enhanced magnetic resonance signals.

The rational design of theranostic nanoparticles exhibiting synergistic turn-on of therapeutic potency and enhanced diagnostic imaging in response to tumor milieu is critical for efficient personalized cancer chemotherapy. We herein fabricate self-reporting theranostic drug nanocarriers based on hyperbranched polyprodrug amphiphiles (hPAs) consisting of hyperbranched cores conjugated with reduction-activatable camptothecin prodrugs and magnetic resonance (MR) imaging contrast agent (Gd complex), and hydrophilic coronas functionalized with guanidine residues. Upon cellular internalization, reductive milieu-actuated release of anticancer drug in the active form, activation of therapeutic efficacy (>70-fold enhancement in cytotoxicity), and turn-on of MR imaging (∼9.6-fold increase in T1 relaxivity) were simultaneously achieved in the simulated cytosol milieu. In addition, guanidine-decorated hPAs exhibited extended blood circulation with a half-life up to ∼9.8 h and excellent tumor cell penetration potency. The hyperbranched chain topology thus provides a novel theranostic polyprodrug platform for synergistic imaging/chemotherapy and enhanced tumor uptake.

Hyperbranched Self-Immolative Polymers (hSIPs) for Programmed Payload Delivery and Ultrasensitive Detection.

Upon stimuli-triggered single cleavage of capping moieties at the focal point and chain terminal, self-immolative dendrimers (SIDs) and linear self-immolative polymers (l-SIPs) undergo spontaneous domino-like radial fragmentation and cascade head-to-tail depolymerization, respectively. The nature of response selectivity and signal amplification has rendered them a unique type of stimuli-responsive materials. Moreover, novel design principles are required for further advancement in the field of self-immolative polymers (SIPs). Herein, we report the facile fabrication of water-dispersible SIPs with a new chain topology, hyperbranched self-immolative polymers (hSIPs), by utilizing one-pot AB2 polycondensation methodology and sequential postfunctionalization. The modular engineering of three categories of branching scaffolds, three types of stimuli-cleavable capping moieties at the focal point, and seven different types of peripheral functional groups and polymeric building blocks affords both structurally and functionally diverse hSIPs with chemically tunable amplified-release features. On the basis of the hSIP platform, we explored myriad functions including visible light-triggered intracellular release of peripheral conjugated drugs in a targeted and spatiotemporally controlled fashion, intracellular delivery and cytoplasmic reductive milieu-triggered plasmid DNA release via on/off multivalency switching, mitochondria-targeted fluorescent sensing of H2O2 with a detection limit down to ∼20 nM, and colorimetric H2O2 assay via triggered dispersion of gold nanoparticle aggregates. To further demonstrate the potency and generality of the hSIP platform, we further configure it into biosensor design for the ultrasensitive detection of pathologically relevant antigens (e.g., human carcinoembryonic antigen) by integrating with enzyme-mediated cycle amplification with positive feedback and enzyme-linked immunosorbent assay (ELISA).

Reversibly Switching Bilayer Permeability and Release Modules of Photochromic Polymersomes Stabilized by Cooperative Noncovalent Interactions.

We report on the fabrication of photochromic polymersomes exhibiting photoswitchable and reversible bilayer permeability from newly designed poly(ethylene oxide)-b-PSPA (PEO-b-PSPA) diblock copolymers, where SPA is spiropyran (SP)-based monomer containing a unique carbamate linkage. Upon self-assembling into polymersomes, SP moieties within vesicle bilayers undergo reversible phototriggered isomerization between hydrophobic spiropyran (SP, λ2 > 450 nm irradiation) and zwitterionic merocyanine (MC, λ1 < 420 nm irradiation) states. For both SP and MC polymersomes, their microstructures are stabilized by multiple cooperative noncovalent interactions including hydrophobic, hydrogen bonding, π-π stacking, and paired electrostatic (zwitterionic) interactions, with the latter two types being exclusive for MC polymersomes. Control experiments using analogous block copolymers of hydrophobic SP monomer with a carbonate linkage (SPO) and conventional spiropyran methacrylate monomer (SPMA) containing a single ester functionality were then conducted, revealing that carbamate-incurred hydrogen bonding interactions in PEO-b-PSPA are crucial for polymersome stabilization in the zwitterionic MC state. Moreover, reversible phototriggered SP-to-MC polymersome transition is accompanied by membrane polarity and permeability switching from being nonimpermeable to selectively permeable toward noncharged, charged, and zwitterionic small molecule species below critical molar masses. Intriguingly, UV-actuated MC polymersomes possess two types of release modules: (1) sustained release upon short UV irradiation duration by taking advantage of the unexpectedly slow spontaneous MC-to-SP transition kinetics (t1/2 > 20 h) under dark conditions; (2) on-demand and switchable release under alternated UV-vis light irradiation. We further demonstrate photoswitchable spatiotemporal release of 4',6-diamidino-2-phenylindole (DAPI, cell nuclei-staining dye) within living HeLa cells.