Rana Sanyal

Bacterial infection is one of the major challenges in wound healing. The emergence of multidrug‐resistant microorganisms has limited the effectiveness of conventional therapeutic agents, such as antibiotics, for wound treatment, highlighting the need for alternative antibacterial strategies. Among these emerging approaches, photothermal therapy (PTT) has attracted significant attention because of its ability to eradicate pathogenic microorganisms through localized heat generation upon near‐infrared (NIR) irradiation. Moreover, PTT can minimize systemic toxicity and potentially reduce the development of antimicrobial resistance, since in most applications it is localized and in general does not utilize conventional antibiotics. Organic, inorganic, and hybrid photothermal agents incorporated into gel‐based platforms can further enhance therapeutic efficacy by enabling localized drug penetration and retention, controlled and on‐demand cargo release upon NIR irradiation, and the creation of a favorable microenvironment for wound healing. This review summarizes recent advances in photothermal hydrogels, microgels, and nanogels for antibacterial applications. Overall, this review provides a comprehensive perspective on the design and fabrication of advanced photothermal antibacterial platforms and highlights their potential for the development of next‐generation therapeutic scaffolds for infected wound management.

Over the past decade, nanogels (NGs) have emerged as a promising drug delivery platform for targeted cancer therapy. Herein, we report the design and fabrication of a multi-functional photosensitizing nanogel system for photodynamic therapy (PDT) based on supramolecularly crosslinked biocompatible polymers. Nanogels were formed via host−guest interactions between β-cyclodextrin (β-CD)-conjugated polymers and a tetravalent adamantane-functionalized zinc phthalocyanine (Ada-TEG-ZnPc). Importantly, the Ada-TEG-ZnPc moiety functions as both a physical crosslinker and a photosensitizer, enabling the one-step assembly of photosensitizing nanogels. Post-assembly supramolecular functionalization with an adamantane-conjugated integrin-targeting peptide yielded cancer cell-targeting nanogels. It is demonstrated that both Ada-TEG-ZnPc and the resulting nanogels generated singlet oxygen efficiently upon light irradiation. In vitro studies using MDA-MB-231 breast cancer cells confirmed effective cellular internalization of both targeted and nontargeted nanogels, while enhanced uptake was observed for targeting peptide-functionalized systems. Reactive oxygen species generation within cells was confirmed, and pronounced phototoxicity was observed under light irradiation, with no dark toxicity. Overall, the targeted photodynamic nanogels exhibited high efficacy, highlighting the potential of supramolecular macromolecular design for targeted PDT applications.

Stimuli-responsive polymer–drug conjugates (PDCs) offer a powerful platform to enhance therapeutic precision in cancer treatment by enabling controlled and context-specific drug release. Herein, we report the rational design of dual-drug copolymeric systems incorporating gemcitabine (GEM) and hydroxychloroquine (HCQ), in which linker chemistry is systematically engineered to modulate drug release profiles and therapeutic efficacy. A library of copolymers featuring ester, carbamate, carbonate, and disulfide-containing linkages was synthesized to evaluate the impact of chemical connectivity on drug liberation and cytotoxic performance in pancreatic adenocarcinoma models. Comparative release studies revealed that incorporation of a redox-responsive disulfide–carbamate linker significantly enhances GEM release relative to carbamate alone, while carbonate linkages provide superior release of HCQ compared to ester and carbamate analogues. These findings underscore the critical role of orthogonal linker selection in independently tuning the release kinetics of multiple payloads within a single macromolecular construct. Among the synthesized polymer drug conjugates, P(OEG/HCQ-CB/GEM-SS-C) copolymer exhibited the most promising performance, demonstrating efficient drug release and enhanced cytotoxicity against pancreatic cancer cells, and it was chosen for further evaluation. Biological evaluation demonstrated efficient cellular internalization of this optimized system in both BxPC-3 monolayers and 3D spheroids, as evidenced by time-dependent increases in fluorescence intensity using a BODIPY-labeled analogue. Collectively, this study highlights a modular linker-engineering strategy to achieve spatiotemporally controlled codelivery of synergistic therapeutics and identifies a promising dual-drug PDC candidate for further preclinical development against pancreatic cancer.

In recent years, there has been remarkable progress in designing drug delivery systems since the dawn of polymer therapeutics. Advances in polymer science and bioconjugation chemistry continue to advance the design and efficiency of drug delivery systems. Among the various drug delivery systems, polymeric micelles stand out because of their versatile features, like increased bioavailability of hydrophobic therapeutic cargo, as well as enhanced uptake in tumors because of their nanosize-mediated passive targeting. Importantly, the polymeric micelles can be engineered to actively target disease sites through surface functionalization with appropriate bioactive ligands. Decorating the micelle surface with bioactive ligands has emerged as one of the most preferred approaches to enhance their targeting capability. Over the years, many ligands have been explored for active targeting, ranging from sugars and peptides to antibodies and oligonucleotides. Progress in protein sciences and molecular biology continues to reveal new ligands and enlarge this library. Considering the delicate nature of the biological ligands, the utilization of mild, efficient, and benign chemical transformations is vital. In this context, the advent of “click” chemistry has dramatically altered the design of targeted micelles. The ability to modify polymers with “clickable” handles at the desired locations, as well as control over the density of these reactive units, expands the utilization of this chemistry. Over the years, the focus has shifted from the highly efficient copper-catalyzed azide–alkyne cycloaddition to “metal-free click” reactions. Additionally, bioorthogonal “click” reactions have enabled the achievement of “in vivo click” transformation-based targeting strategies either through metabolic glycoengineering or stimuli-induced aggregation. This review focuses on the advances in the fabrication of ligand-based targeted micelles using the “click” reaction for ligand conjugation onto polymeric micelles and highlights recent applications of these materials for targeted drug delivery.

Polymer brushes engineered to "specifically capture" and "release on demand" analytes such as dyes, proteins, and cells find biomedical applications ranging from protein immobilization to cell death. Utilizing a disulfide-linker-containing monomer as a building block enables the fabrication of a redox-responsive polymer brush platform with the "catch and release" attribute. Herein, thiol-reactive redox-responsive polymer brushes are fabricated using a pyridyl disulfide-based monomer, and their postpolymerization functionalization is demonstrated via thiol-disulfide exchange reaction with thiol-containing dyes, (bio)molecules, and cell adhesive ligands. After establishing reversible conjugation using a fluorescent dye and other model compounds, copolymer brushes postmodified with thiol-containing mannose demonstrated selective immobilization of concanavalin A in the presence of peanut agglutinin. In addition, a thiolated RGD peptide was conjugated to the side chain of polymer brushes to facilitate cell adhesion, followed by on-demand harvesting. To enable localized drug delivery to surface-adhered cells, orthogonal chain end and side chain functionalization using the thiol-Michael addition and thiol-disulfide exchange reaction, respectively, was used to conjugate the cell adhesive RGD peptide and the anticancer drug doxorubicin (DOX). On-demand DOX release and internalization by surface-bound cancer cells were demonstrated via cleavage of disulfide linkages in the presence of a reducing agent. This approach may provide an attractive methodology to deliver therapeutic agents precisely to specific cells.

A modular approach to install functional chain-end groups through a redox-responsive disulfide linkage is utilized to fabricate a targeted delivery system using self-assembly.

Polymer brush-coated magnetic nanoparticles find applications in areas from diagnostics to drug delivery. Generally, the brushes are irreversibly tethered onto the nanoparticle surface through robust chemical linkages to withstand diverse environments. The ability to trigger the release of the polymer brushes from the nanoparticle surface once they reach the intracellular environment would be a useful attribute. In this study, we report polymer brushes that undergo release from the nanoparticle surface in a redox-responsive fashion. Furthermore, cleaving the polymer brush also enables precise determination of their molecular weight. Also, we show that fluorescently labeled polymer brushes undergo chain-end functionalization using maleimide-containing dye and peptides. Installing integrin-targeting peptides onto the surface enhances their cellular internalization. One could envision that the redox-responsive polymer brush-coated magnetic nanoparticles disclosed here would be an attractive platform for applications where intracellular cleavage of polymeric chains would enhance their performance.

Macroporous cryogels are attractive scaffolds for biomedical applications, such as biomolecular immobilization, diagnostic sensing, and tissue engineering. In this study, thiol-reactive redox-responsive cryogels with a porous structure are prepared using photopolymerization of a pyridyl disulfide poly(ethylene glycol) methacrylate (PDS-PEG-MA) monomer. Reactive cryogels are produced using PDS-PEG-MA and hydrophilic poly(ethylene glycol) methyl ether methacrylate (PEGMEMA) monomers, along with a PEG-based cross-linker and photoinitiator. Functionalization of cryogels using a fluorescent dye via the disulfide-thiol exchange reactions is demonstrated, followed by release under reducing conditions. For ligand-mediated protein immobilization, first, thiol-containing biotin or mannose is conjugated onto the cryogels. Subsequently, fluorescent dye-labeled proteins streptavidin and concanavalin A (ConA) are immobilized via ligand-mediated conjugation. Furthermore, we demonstrate that the mannose-decorated cryogel could capture ConA selectively from a mixture of lectins. The efficiency of protein immobilization could be easily tuned by changing the ratio of the thiol-sensitive moiety in the scaffold. Finally, an integrin-binding cell adhesive peptide is attached to cryogels to achieve successful attachment, and the on-demand detachment of integrin-receptor-rich fibroblast cells is demonstrated. Redox-responsive cryogels can serve as potential scaffolds for a variety of biomedical applications because of their facile synthesis and modification.