Aug 2026· Materials· Vol 19· 0 citations· 185 references
Medicine
TL;DR
A sophisticated blueprint for the next generation of nature-derived, “intelligent” biomaterials in cancer therapy is provided, providing a sophisticated blueprint for the next generation of nature-derived, “intelligent” biomaterials in cancer therapy.
Abstract
Stimuli-responsive drug-delivery systems (SRDDS) have transformed precision medicine by enabling spatiotemporal control over therapeutic release, significantly reducing off-target toxicity while enhancing efficacy at the disease site. Naturally occurring polysaccharides, such as hyaluronic acid, chitosan, alginate, and dextran stand out as premier scaffolds for these “smart” nanoplatforms due to their inherent biocompatibility, biodegradability, and abundance of reactive sites for molecular engineering. This review explores the versatility of polysaccharide functionalization, detailing how the introduction of molecular “switches” allows these biopolymers to sense and respond to specific physiological triggers. We analyze the mechanisms behind acid–labile bonds for pH-triggered release, redox-sensitive bridges for intracellular delivery, and enzyme-cleavable sequences for bio-catalytic activation. By bridging the gap between molecular functionalization and clinical utility, these bio-responsive polysaccharide architectures enable integrated physiological monitoring and theranostic applications. This review highlights the impact of these advancements in overcoming biological barriers, providing a sophisticated blueprint for the next generation of nature-derived, “intelligent” biomaterials in cancer therapy.
This review critically evaluates the design parameters of biopolymer delivery systems, focusing on the optimization of particle size and drug loading capacity and addresses key translational hurdles, including the biological limitations of active targeting and safety concerns like complement activation-related pseudoallergy.
The study highlights the promising applications of smart polymers in precision medicine, allowing for targeted therapeutic interventions that are more effective and less harmful to the body.
Varleen Kaur, Dr. Ashish Narain Dubey· Naveen International Journal...· 0 citations
Target-specific strategies are essential for the success of modern drug therapy in terms of safety and effectiveness. Thus, drug delivery must extend beyond tissue-level targeting to intracellular targeting, which is the ultimate site of action. Cell-penetrating peptides (CPPs) have therefore emerged as an approach to deliver drugs into target cells, yet concerns remain regarding cytotoxicity and limited targeting precision. In this context, we investigated biodynamers as a new class of pH-responsive CPPs. Biodynamers are dynamic peptide analogs, composed of amino acid-hydrazides together with a hexaethylene glycol-conjugated carbazole dialdehyde monomer. Each monomer is linked through pH-sensitive dynamic covalent bonds. Therefore, under acidic conditions, these polymers undergo structural rearrangements, including changes in molecular weight and conformation, potentially influencing their pH-dependent uptake. We synthesized three biodynamers with varying Lys-to-Arg ratios and evaluated their uptake in A549 and SW480 cells by pH. All biodynamers exhibited significantly higher uptake in acidic media (pH 6.0, HBSS) compared to neutral conditions at pH 7.4. This acid-induced uptake appears to be promoted by the enhanced electrostatic interactions between the biodynamers and the cell membrane, driven by dynamic degradation of the biodynamer under acidic conditions. Such degradation increases the number of terminal amino groups, thereby elevating charge density. Furthermore, circular dichroism results indicate a conformational change is induced under acidic conditions, which likely contributes to the enhanced cellular internalization as seen with conventional CPPs. Collectively, the biodynamers offer insight into a potential strategy to further enhance the selectivity of cell-penetrating agents for drug delivery in acidic disease microenvironments.
Philippe Sonntag, Mohamed A. M. Kamal, Camilla Passi et al.· Discover Polymers· 0 citations
A new Triple-Stimuli Release Model is presented that provides a computational experimental bridge to expedite preclinical validation while mathematically forecasting concurrent release kinetics and how well molecular dynamics simulations and artificial intelligence combine to forecast toxicity, drug-carrier interactions and nanocomposite stability are assessed.
H. Hashemi, Aref Zahiri Ghareh Mosa, Ketevan Tavamaishvili et al.· Discover Applied Sciences· 0 citations
INTRODUCTION
Polysaccharide hydrogels have gained increasing attention as innovative platforms for controlled and stimuli-responsive drug delivery. Inherent biocompatibility, biodegradability and chemical versatility of these materials render them particularly well-suited for biomedical applications. Moreover, their ability to be engineered into 'smart' systems facilitates controlled release of therapeutic agents at target sites. This review summarizes recent advances in synthesis strategies and functional properties of polysaccharide hydrogels relevant for drug delivery.
AREAS COVERED
Mechanical tunability, responsiveness to physiological stimuli and affinity-based interactions are analyzed with regards to their impact on therapeutic efficacy. Key hurdles such as manufacturing scalability, reproducibility, regulatory compliance, challenge of balancing biodegradability with mechanical stability and controlled drug release are critically discussed. Proof-of-concept studies are highlighted spanning preclinical in vivo models, as well as early clinical trials exploring application in oncology, regenerative medicine and pain management.
EXPERT OPINION
Polysaccharide-based stimuli-responsive and multifunctional hydrogels represent highly promising platforms for controlled and targeted drug delivery. While recent advances in biofabrication and nanotechnology have significantly expanded their therapeutic potential, important challenges including scalability, reproducibility, and clinical translation, still need to be addressed. In particular, limited availability of long-term in vivo safety and efficacy data remains a major barrier to broader clinical application.
Gioconda Millotti, Flavia Laffleur, Agnes Kestler· Expert Opinion on Drug Deliv...· 0 citations
Alginate-based hydrogels have emerged as versatile biomaterials because of their biocompatibility, high water content, mild aqueous processing, and tunable network architecture. However, their performance is strongly dependent on molecular characteristics, including molecular weight, mannuronic-to-guluronic acid (M/G) ratio, block distribution, degree of functionalization, and crosslinking density. This review critically examines how these parameters govern the physicochemical, mechanical, biological, and translational performance of alginate-based nanostructured hydrogels. Particular emphasis is placed on ionotropic gelation, covalent functionalization, oxidation, sulfation, grafting, and hybrid covalent-ionic crosslinking, together with nanocomposite reinforcement and advanced biofabrication strategies. Recent studies demonstrate that controlling network architecture and nanoscale organization can substantially improve mechanical stability, degradation behavior, drug-loading and release characteristics, cellular interactions, and tissue-regeneration performance. For example, re-cent alginate systems have achieved optimized pore dimensions in the ∼100-200 μm range for cell-supporting scaffolds, drug encapsulation efficiencies approaching or exceeding 90% in selected nanostructured systems, and high cell viability (>95%) in representative double-network hydrogel platforms. The review further identifies persistent challenges involving source-to-source variability, batch reproducibility, ion exchange, insufficient intrinsic bioactivity, controlled degradation, sterilization, and clinical translation. Finally, future opportunities are discussed in stimulus-responsive networks, hierarchical biofabrication, multifunctional nanocomposites, sustainable alginate extraction, and data-driven structure-property optimization. The review establishes a structure-processing-property-biological performance framework for the rational design of next-generation alginate-based nanostructured hydrogels.
Abdullah Khamis Ali Al Saidi, E. Abu Zeitoun, M. Ul-Islam et al.· Carbohydrate Research· 0 citations
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