Constructing Ultra-Strong SERS Tags in the Cellular Raman-Silent Region by Orthogonal Array Testing Strategy.

Surface-enhanced Raman spectroscopy (SERS) tags have the advantages of unique fingerprint vibration spectrum, ultranarrow spectral line widths, and weak photobleaching effect, showing great potential for bioimaging. However, SERS imaging is still hindered for further application due to its weak spontaneous Raman scattering, biomolecular signal interference, and long acquisition times. Here, we develop a novel SERS tag of the core (Au)-shell (N-doped graphene) structure (Au@NGs) with ultrastrong and stable Raman signal (2180 cm-1) in the cellular Raman-silent region (1800-2800 cm-1) through base-promoted oxidative decarboxylation of amino acids. Exploring the factors (metal salts, amino acids, catalysts, temperature, etc.) to obtain Au@NGs with the strongest Raman signal commonly requires more than 100,000 separate experiments, while that using an orthogonal array testing strategy is reduced to 56. The existence of deep charge transfer between the Au surface and C≡N-graphene is proved by theoretical calculations, which means the ultrastrong signal of Au@NGs is the joint effect of electromagnetic and chemical enhancement. The Au@NGs have a detection sensitivity down to a single-nanoparticle level, and high-speed and high-resolution cellular imaging (4453 pixels) is obtained within 10 s by global Raman imaging. The combination of Au@NGs-based tags with ultrastrong intrinsic Raman imaging capability and global imaging technology holds great promise for high-speed Raman imaging.

Biological characteristics of pregnancy in captive Yangtze finless porpoises revealed by urinary metabolomics†.

The Yangtze finless porpoises (Neophocaena asiaeorientalis a.) are an endemic and critically endangered species in China. Intensive captive breeding is essential for understanding the biology of critically endangered species, especially their pregnancy characteristics, knowledge of which is crucial for effective breeding management. Urine metabolomics can reveal metabolic differences, arising from physiological changes across pregnancy stages. Therefore, we used the urinary metabolomic technology, to explore urinary metabolite changes in pregnant Yangtze finless porpoises. A total of 2281 metabolites were identified in all samples, which including organic acids and derivatives (24.45%), organoheterocyclic compounds (20.23%), benzenoids (18.05%), organic oxygen compounds (7.73%), and phenylpropanoids and polyketides (6.48%). There were 164, 387, and 522 metabolites demonstrating differential abundance during early pregnancy, mid pregnancy, and late pregnancy, respectively, from the levels observed in nonpregnancy. The levels of pregnenolone, 17α-hydroxyprogesterone, and tetrahydrocortisone were significantly higher during all pregnancy stages, indicating their important roles in fetal development. The differential metabolites between nonpregnancy and pregnancy were mainly associated with amino acid and carbohydrate metabolism. Moreover, metabolic activity varied across pregnancy stages; steroid hormone biosynthesis was predominant in early pregnancy, and amino acid biosynthesis and carbohydrate metabolism were predominant in mid pregnancy and late pregnancy, respectively. Our results provide new insights into metabolic characteristics in the Yangtze finless porpoises' urine during pregnancy, and indicate that the differential levels of urine metabolites can determine pregnancy in Yangtze finless porpoises, providing valuable information for the husbandry and management of pregnant Yangtze finless porpoises in captivity.

Click to Self-immolation: A "Click" Functionalization Strategy towards Triggerable Self-Immolative Homopolymers and Block Copolymers.

Self-immolative polymers (SIPs) are a class of degradable macromolecules that undergo stimuli-triggered head-to-tail depolymerization. However, a general approach to readily end-functionalize SIP precursors for programmed degradation remains elusive, restricting access to complex, functional SIP-based materials. Here we present a "click to self-immolation" strategy based on aroyl azide-capped SIP precursors, enabling the facile construction of diverse SIPs with different trigger units through a Curtius rearrangement and alcohol/thiol-isocyanate "click" reaction. This strategy is also applied to polymer-polymer coupling to access fully depolymerizable block copolymer amphiphiles, even combining different SIP backbones. Our results demonstrate that the depolymerization can be actuated efficiently under physiologically-relevant conditions by the removal of the trigger units and ensuing self-immolation of the p-aminobenzyl carbonate linkage, indicating promise for controlled release applications involving nanoparticles and hydrogels.

Coordinating External and Built-In Triggers for Tunable Degradation of Polymeric Nanoparticles via Cycle Amplification.

The selective activation of nanovectors in pathological tissues is of crucial importance to achieve optimized therapeutic outcomes. However, conventional stimuli-responsive nanovectors lack sufficient sensitivity because of the slight difference between pathological and normal tissues. To this end, the development of nanovectors capable of responding to weak pathological stimuli is of increasing interest. Herein, we report the fabrication of amphiphilic polyurethane nanoparticles containing both external and built-in triggers. The activation of external triggers leads to the liberation of highly reactive primary amines, which subsequently activates the built-in triggers with the release of more primary amines in a positive feedback manner, thereby triggering the degradation of micellar nanoparticles in a cycle amplification model. The generality and versatility of the cycle amplification concept have been successfully verified using three different triggers including reductive milieu, light irradiation, and esterase. We demonstrate that these stimuli-responsive nanoparticles show self-propagating degradation performance even in the presence of trace amounts of external stimuli. Moreover, we confirm that the esterase-responsive nanoparticles can discriminate cancer cells from normal ones by amplifying the esterase stimulus that is overexpressed in cancer cells, thereby enabling the selective release of encapsulated payloads and killing cancer cells. This work presents a robust strategy to fabricate stimuli-responsive nanocarriers with highly sensitive property toward external stimuli, showing promising applications in cancer therapy with minimized side effects.

Enhancing autotrophic nitrogen removal with a novel dissolved oxygen-differentiated airlift internal circulation reactor: Long-term operational performance and microbial characteristics.

Autotrophic nitrogen removal (ANR) processes have not been widely applied in wastewater treatment due to their long start-up time and unstable performance. In this study, a novel dissolved oxygen-differentiated airlift internal circulation reactor was developed to enhance ANR from wastewater. During 200 days of continuous operation, the reactor start-up was achieved within 30 days; a high total nitrogen removal efficiency of 80% was achieved and stably maintained under an aeration rate of 0.90 L/min and hydraulic retention time of 6 h. Additionally, the color of sludge went from a light yellow to dark red, and the amount and size of the micro-granules increased obviously. Medium-sized (1.0-2.5 mm) micro-granules accounted for 72.4% on day 190. The specific anammox activity increased from 0.53 to 1.43 g-N/g-VSS/d, while the SNOA decreased from 0.93 to 0.08 g-N/g-VSS/d. Furthermore, the microbial analysis showed that the Nitrosomonas (4.2%) and Candidatus Brocadia (22.6%) were enriched and formed the micro-granules after the reactor's long-term operation. The results indicate that novel configuration realizes the partitioning of dissolved oxygen (DO), optimizes nitritation and anammox reactions, and accelerates biochemical reactions, thereby enhancing ANR performance. This study provides a practical alternative to enhance ANR performance and a scientific basis for the development and application of novel nitrogen removal reactors.

Molecularly Engineering Triptolide with Aptamers for High Specificity and Cytotoxicity for Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) lacks three important receptors, ER, PR, and HER2. It is more aggressive and more likely to relapse after treatment, thus has been identified as one of the most malignant breast cancer types. The development of efficient targeted TNBC therapy is an important research topic in TNBC treatment. We report the development of a new aptamer-drug conjugate (ApDC), AS1411-triptolide conjugate (ATC), as targeted therapy for the treatment of TNBC with high efficacy. The conjugate possesses excellent specificity and high cytotoxicity against the MDA-MB-231 cell line. The advantages of our newly invented ATC are further highlighted by its excellent in vivo anti-TNBC efficacy and negligible side effects toward healthy organs.

Conjugating Aptamer and Mitomycin C with Reductant-Responsive Linker Leading to Synergistically Enhanced Anticancer Effect.

Mitomycin C (MMC) has been using for the treatment of a variety of digestive tract cancers. However, its nonspecific DNA-alkylating ability usually causes severe side effects, thus largely limiting its clinical applications. The utilization of an efficient active targeted drug delivery technique would address this issue. Accordingly, we report the design and development of aptamer-mitomycin C conjugates that use different cross-linking chemistry. The targeted delivery ability and cytotoxicity of these conjugates were carefully studied. It is worth noting that a linker-dependent cytotoxicity effect was observed for these conjugates. The use of a reductant-sensitive disulfide bond cross-linking strategy resulted in significantly enhanced cytotoxicity of MMC against the target cancer cell lines. Importantly, this cytotoxicity enhancement was suited to different types of aptamers, demonstrating the success of our design. Mechanistic studies of the enhanced cytotoxicity effect indicated that the target recognition, specific binding, and receptor-mediated internalization of aptamer were also critical for the observed effect.

Polymeric Engineering of Aptamer-Drug Conjugates for Targeted Cancer Therapy.

Nucleic acid aptamers, also known as "chemical antibodies", have been widely employed in targeted cancer therapy and diagnosis. For example, aptamer-drug conjugates (ApDCs), through covalent conjugation of cytotoxic warheads to aptamers, have demonstrated anticancer efficacy both in vitro and in vivo. However, a general strategy to endow ApDCs with enhanced biostability, prolonged circulation half-life, and high drug loading content remained elusive. Herein, we present a polymeric approach to engineer ApDCs via conjugation of cell-targeting aptamers with water-soluble polyprodrugs containing a reductive environmentally sensitive prodrug and biocompatible brush-like backbone. The resultant high-drug loading Aptamer-PolyproDrug Conjugates (ApPDCs) exhibited high nuclease resistance, extended in vivo circulation time, specific recognition, and cellular uptake to target cells, reduction-triggered and fluorescent-reporting drug release, and effective cytotoxicity. We could also further expand this design principle toward combination therapy by using two kinds of therapeutic drugs with distinct pharmacological mechanisms.

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.

Reduction-Triggered Transformation of Disulfide-Containing Micelles at Chemically Tunable Rates.

A dilemma exists between the circulation stability and cargo release/mass diffusion at desired sites when designing delivery nanocarriers and in vivo nanoreactors. Reported herein are disulfide-crosslinked (DCL) micelles exhibiting reduction-triggered switching of crosslinking modules and synchronized hydrophobic-to-hydrophilic transition. Tumor cell targeted DCL micelles undergo cytoplasmic milieu triggered disulfide cleavage and self-immolative decaging reactions at chemically adjustable rates, generating primary amine moieties. Extensive amidation reactions with neighboring ester moieties then occur because of the high local concentration and suppression of the apparent amine pKa  value within the hydrophobic cores, thus leading to the transformation of crosslinking modules and formation of tracelessly crosslinked (TCL) micelles, with hydrophilic cores, inside live cells. We further integrate this design principle with theranostic nanocarriers for selective intracellular drug transport guided by enhanced magnetic resonance (MR) imaging performance.

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.

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.

Incorporating ecosystem services into functional zoning and adaptive management of natural protected areas as case study of the Shennongjia region in China.

Against the background of global climate change and anthropogenic interference, studying the spatial and temporal heterogeneity of ecosystem services in important ecological function regions and rationally dividing the functional zones will help to promote the construction of the natural protected areas system dominated by national parks. The Shennongjia Region is an important candidate for China's national parks and one of the key pilots. Integrating the InVEST model, Getis-Ord Gi* index, hotspot analysis, GeoDetector and K-means clustering algorithm, we measured five ecosystem services interactions and delineate the functional zones. The results show that the spatial and temporal evolution of various ecosystem services in the Shennongjia Region between 2000 and 2020 was significant. All ecosystem services showed a decreasing and then increasing trend, except for carbon storage, which slowly declined. The ecological status of the region is in the process of polarization, with the local environment showed a trend of continuous deterioration. Water yield-habitat quality and carbon storage-water purification showed synergistic relationships; soil conservation showed trade-offs with water yield, carbon storage and water purification over a wide spatial range. The interaction between land surface temperature and vegetation cover was the most significant dominant factor. Hot spots for the comprehensive ecosystem services index were mainly located in the central and southern parts of the Shennongjia region and four types of ecosystem service functional zones were identified accordingly. This study is of great significance for maximizing the benefits of ecosystem service functions, the efficient allocation of environmental resources and the rational formulation of management policies in natural protected areas.

Emerging Trends in the Chemistry of End-to-End Depolymerization.

Over the past couple of decades, polymers that depolymerize end-to-end upon cleavage of their backbone or activation of a terminal functional group, sometimes referred to as "self-immolative" polymers, have been attracting increasing attention. They are of growing interest in the context of enhancing polymer degradability but also in polymer recycling as they allow monomers to be regenerated in a controlled manner under mild conditions. Furthermore, they are highly promising for applications as smart materials due to their ability to provide an amplified response to a specific signal, as a single sensing event is translated into the generation of many small molecules through a cascade of reactions. From a chemistry perspective, end-to-end depolymerization relies on the principles of self-immolative linkers and polymer ceiling temperature (Tc). In this article, we will introduce the key chemical concepts and foundations of the field and then provide our perspective on recent exciting developments. For example, over the past few years, new depolymerizable backbones, including polyacetals, polydisulfides, polyesters, polythioesters, and polyalkenamers, have been developed, while modern approaches to depolymerize conventional backbones such as polymethacrylates have also been introduced. Progress has also been made on the topological evolution of depolymerizable systems, including the introduction of fully depolymerizable block copolymers, hyperbranched polymers, and polymer networks. Furthermore, precision sequence-defined oligomers have been synthesized and studied for data storage and encryption. Finally, our perspectives on future opportunities and challenges in the field will be discussed.

Regulating the properties of XQ-2d for targeted delivery of therapeutic agents to pancreatic cancers.

Enhanced recognition ability, cell uptake capacity, and biostability are characteristics attributed to aptamer-based targeted anticancer agents, and are possibly associated with increased accumulation at the tumor site, improved therapeutic efficacy and reduced negative side effects. Herein, a phosphorothioate backbone modification strategy was applied to regulate the biomedical properties of pancreatic cancer cell-targeting aptamer for efficient in vivo drug delivery. Specifically, the CD71- targeting aptamer XQ-2d was modified into a fully thio-substituted aptamer S-XQ-2d, improving the plasma stability of S-XQ-2d and mitomycin C (MMC)-functionalized S-XQ-2d (MFSX), thus considerably prolonging their half-life in mice. Moreover, the binding and uptake capacities of S-XQ-2d were significantly enhanced. MFSX showed the same level of cytotoxicity as that of MMC against targeted cancer cells, but lower toxicity to non-targeted cells, highlighting its specificity and biosafety. Brief mechanistic studies demonstrated that XQ-2d and S-XQ-2d had different interaction modes and internalization pathways with the targeted cells.

Insight into the pollution characteristics of road and roof runoff in Changsha, China.

Non-point source pollution from rainwater runoff presents a serious challenge for urban water management in many cities undergoing urbanization and experiencing climate change. To alleviate water resource conflicts in Changsha, China, this study comprehensively evaluated the pollution characteristics and first flush effect (FFE) of runoff from asphalt roads and colored steel plate roofs under seven rainfall events in April-May 2022. The runoff was collected and purified using bioretention ponds. The results showed that the peak runoff pollutant concentrations occurred within the first 20 min of runoff generation and then decreased to relatively stable levels, with maximum total suspended solids (TSS) concentration and chemical oxygen demand (CODCr) reaching 873.5 and 207.32 mg/L, respectively, for road runoff and 162 and 73.31 mg/L for roof runoff, respectively. The main pollutants were TSS and CODCr, followed by ammonia nitrogen (NH4+-N), nitrate nitrogen (NO3--N), total phosphorus (TP), and nitrite nitrogen (NO2--N). Concentrations of pollutants and FFE for roof runoff were lower than those for road runoff. Road runoff had a more obvious FFE for TP and NH4+-N, whereas the roof runoff showed the presence of TP and NO3--N. An important implication is that treating the first 30% of surface runoff from rainfall events with long antecedent dry days or high rainfall amounts is necessary to improve water quality before discharge or utilization. The study also found that road and roof runoff, after treatment with bioretention ponds, exhibit good water quality, thus, allowing their use as reclaimed water or for miscellaneous purposes in urban areas. Overall, this study provides useful information for designing management measures to mitigate runoff pollution and reuse in Changsha.

Digital micelles of encoded polymeric amphiphiles for direct sequence reading and ex vivo label-free quantification.

Identification and quantification of synthetic polymers in complex biological milieu are crucial for delivery, sensing and scaffolding functions, but conventional techniques based on imaging probe labellings only afford qualitative results. Here we report modular construction of precise sequence-defined amphiphilic polymers that self-assemble into digital micelles with contour lengths strictly regulated by oligourethane sequences. Direct sequence reading is accomplished with matrix-assisted laser desorption/ionization (MALDI) tandem mass spectrometry, facilitated by high-affinity binding of alkali metal ions with poly(ethylene glycol) dendrons and selective cleavage of benzyl-carbamate linkages. A mixture of four types of digital micelles could be identified, sequence-decoded and quantified by MALDI and MALDI imaging at cellular, organ and tissue slice levels upon in vivo administration, enabling direct comparison of biological properties for each type of digital micelle in the same animal. The concept of digital micelles and encoded amphiphiles capable of direct sequencing and high-throughput label-free quantification could be exploited for next-generation precision nanomedicine designs (such as digital lipids) and protein corona studies.

Spatial and temporal evolution of ecological vulnerability based on vulnerability scoring diagram model in Shennongjia, China.

Shennongjia is one of the most important ecological function areas and ecologically vulnerable zones in the world. With the rapid development of social economies, especially tourism, the ecological environment of Shennongjia has experienced profound changes. Exploring the characteristics and changing trends of ecological environment in Shennongjia will help to analyze the causes of the damage to the ecological environment, and build a vulnerability analysis framework with multi-scale, multi-element, multi-flow, and multi-circulation characteristics, which provides an effective research paradigm and analysis tool for the study of regional ecological vulnerability. With the support of RS and GIS technology, this study uses spatial principal component analysis (SPCA) and the vulnerability scoring diagram (VSD) model to comprehensively and quantitatively analyze the spatial and temporal evolution characteristics and driving forces of ecological vulnerability in Shennongjia from 1996 to 2018. The VSD model was selected to decompose the vulnerability into three components of "exposure-sensitivity-adaptation", and 16 indicators were selected to construct an ecological vulnerability evaluation system in Shennongjia, and the evaluation data were organized in a progressive and detailed way. (1) During the study period, the overall ecological vulnerability of Shennongjia is in a mild vulnerability level, exhibiting differentiation characteristics of high in the northeast and low in the southwest. High vulnerability zones are mainly distributed in the main towns and roads. (2) The risk of ecological vulnerability of the entire region presents the characteristics of continuous decline. (3) Land-use types, population density, and vegetation coverage are the main factors driving the evolution of ecological vulnerability. (4) A high level of coupling coordination exists between ecological vulnerability and landscape patterns. Analyses of the ecological vulnerability of Shennongjia shows that the entire region is in a mild vulnerability level. The extreme vulnerability risk of the ecological environment shows polarization. The evolution of ecological environment in Shennongjia is the result of the interaction between human activities and natural environment. This study offers an effective way to assess ecological vulnerability and provides some strategies and guidance for improving ecological security.

Bacteriophage Lytic Enzyme P9ly as an Alternative Antibacterial Agent Against Antibiotic-Resistant Shigella dysenteriae and Staphylococcus aureus.

Developing new strategies to replace or supplement antibiotics to combat bacterial infection is a pressing task in the field of microbiological research. In this study, we report a lytic enzyme named P9ly deriving from the bacteriophage PSD9 that could infect multidrug-resistant Shigella. This enzyme was identified through whole-genome sequencing of PSD9. The results show that P9ly contains a conserved T4-like_lys domain and belongs to the phage lysozyme family. Recombinant P9ly obtained from protein purification presented biological activity and could digest bacterial cell walls (CW), resulting in the destruction of cell structure and leakage of intracellular components. Furthermore, P9ly exhibited bacteriolytic and bactericidal activity on different strains, especially multidrug-resistant Gram-negative Shigella dysenteriae and Gram-positive Staphylococcus aureus. Additionally, combined use of P9ly with ceftriaxone sodium (CRO) could decrease necessary dose of the antibiotic used and improve the antibacterial effect. In summary, under the current backdrop of extensive antibiotic usage and the continuous emergence of bacterial resistance, this study provides an insight into developing bacteriophage-based antibacterial agents against both Gram-negative and Gram-positive pathogens.

Self-immolative polyplexes for DNA delivery.

Nucleic acids have immense potential for the treatment and prevention of a wide range of diseases, but delivery vehicles are needed to assist with their entry into cells. Polycations can reversibly complex with nucleic acids via ionic interactions to form polyplexes and transport them into cells, but they are still hindered by the need to balance cytotoxicity and delivery effectiveness. In this work, we describe a new self-immolative polyglyoxylamide (PGAm) platform designed to address these challenges by complexing nucleic acids via multivalent interactions in the polymeric form and releasing them upon depolymerization. Nine PGAms were synthesized and characterized, with different end-caps and variable cationic pendent groups. The PGAms underwent depolymerization under mildly acidic conditions, with rates dependent on their pendent groups and end-caps. They complexed plasmid DNA, forming cationic nanoparticles, and released it upon depolymerization. Cytotoxicity assays of the PGAms and polyplexes in HEK 293T cells showed a decrease in toxicity following depolymerization, and all samples exhibited much lower toxicity than a commercial non-degradable linear polyethyleneimine (jetPEI) transfection agent. Transfection assays revealed that selected PGAms provided similar levels of reporter gene expression to jetPEI in vitro with a PGAm analogue of poly[2-(dimethylamino)ethyl methacrylate] having particularly interesting activity that was dependent on depolymerization, along with low cytotoxicity. Overall, these results indicate that end-to-end depolymerization of self-immolative polymers can provide a new and promising tool for nucleic acid delivery.