Nanochitin and Nanochitosan in Pharmaceutical Applications: Innovations, Applications, and Future Perspective

Abstract

Nanochitin is a nanoscale form of chitin—a polysaccharide found in the exoskeletons of crustaceans, insects, and some fungal cell walls—that is newly garnering significant attention in the pharmaceutical space. Its good properties, such as biocompatibility, biodegradability, and an easily adjustable surface, render it attractive for various medical and pharmaceutical applications. Nanochitin, from drug delivery systems and wound-care formulations to vaccine adjuvants and antimicrobial strategies, has demonstrated its strong potential in meeting diverse therapeutic needs. This review covers the background of nanochitin, including methods for its extraction and refining and its principal physicochemical and biological properties. It further discusses various hydrolysis and enzymatic approaches for the structural and functional characterization of nanochitin and highlights some pharmaceutical applications where this biopolymer has been studied. The review also addresses toxicity issues, regulatory matters, and challenges in large-scale industrial production. Finally, it underscores novel avenues of investigation and future opportunities, emphasizing the urgent requirement for standardized production methods, rigorous safety assessment, and interdisciplinary partnerships to maximize nanochitin’s potential in pharmaceutical research, demonstrating the importance of chitin in drug delivery.

1. Introduction

Interest in biopolymers for pharmaceutical and biomedical applications has recently surged, with an increasing focus on chitin and its derivatives [1,2]. Nanochitin, derived from chitin, is a promising biopolymer due to its abundance, sustainability, and unique properties, such as toughness, biodegradability, and high reactivity. It is increasingly being explored for various applications in sustainable and advanced manufacturing, biomedical fields, and environmental solutions; as the second most abundant polysaccharide in nature, chitin is primarily sourced from marine crustaceans, insects, and fungal cell walls [3,4]. The partial or complete deacetylation of chitin produces chitosan—Figure 1, a polycationic biopolymer extensively studied for its biomedical benefits [5]. Nanochitin can form hierarchical structures, ranging from nanofibrils to nanorods, contributing to its mechanical strength and application versatility [6,7]. Although the primary focus of this review is on the nanoscale derivatives of chitin and chitosan, such as nanochitin and nanochitosan, it is essential to provide background on the physicochemical properties and solubility behavior of their parent biopolymers. These characteristics determine the efficiency of nanoscale transformation processes and strongly influence their performance in pharmaceutical applications.

Beyond these well-researched forms, recent advancements in nanotechnology have developed nanochitin, generally referring to chitin fibrils, whiskers, or particles with at least one dimension measuring less than 100 nm [6,7,8].
This is due to the large surface area, mechanical strength, and reactive functional groups of nanochitin compared to the micro or macroscale. These properties are helpful for pharmacy-related applications, including drug delivery, tissue engineering, wound healing, and vaccine formulation [9,10]. Moreover, nanochitin is also biocompatible and biodegradable, and it has demonstrated low toxicity [11], making it a good candidate for the co-delivery of sortable pharmaceutical platforms. Its amphiphilicity is a bolstering agent in environmental applications, such as water purification [7,8,10].

This review highlights recent developments in the use of nanochitin, particularly in pharmaceutical applications. We reviewed and discussed the sources and extraction techniques of nanochitin, the physicochemical modifications that promote its functionality, and key characterization techniques that enable formulation and quality control. In addition, we explore its use in drug delivery, wound healing, immunotherapy, etc. Finally, we consider the regulatory prerequisites, toxicological aspects, and relevant difficulties preventing industrially implemented pharmacy using nanochitin [6,8].

2. Chitin: A Potential Precursor for Nanochitin

2.1. Sources of Chitin

2.1.1. Insects

Insect waste-derived chitin is an alternative resource for food security and biomedicine (Figure 2). This new emerging alternative source has potentially raised low allergenic concerns [12,13,14] and is also being utilized in agriculture and bioplastic production [15].

Chitin is abundant in insect farming’s residual streams, especially in molting skins, and both LC-ECD and LC-MS/MS methods are reliable methods to measure glucosamine content [16]. Mealworm cuticles can also be a potential novel source of chitin and chitosan, as they have a global yield of 31.9% and an efficiency of 85% with enzymatic deproteinization [17].

2.1.2. Fungi Species

Fungal cell walls also provide a vegetarian/vegan-friendly (based on glycoforms) route, particularly appealing in pharmaceutical and biomedical fields where access to animal sources can be restricted [18]. Present in the cell walls of fungi, they play a key role in cell stability and interactions with the environment, making them particularly interesting for biomedical applications, such as targeted drug delivery or vaccine development (Figure 2) [19].

In fungi, the regulation of chitin synthesis plays an essential role in maintaining the cell wall integrity and modulating host immune responses to fungal pathogens [20]. For this reason, fungal chitin recognition by the human immune system may help limit inflammation during fungal infections and help return immunity to a balanced state following pathogen clearance [21]. Disruption of gut fungal microbiota composition is correlated with mucosal inflammation and disease activity in patients with Crohn’s disease [22]. Intestinal microbiota dysbiosis was found in Chinese Crohn’s disease patients, manifesting high levels of pathogenic bacteria and low levels of beneficial bacterial species [23]. Table 1 shows some species that produce chitin.

2.1.3. Crustacean Shells

The most popular plankton source for chitin is crustacean shells [4,28,29,30,31,32]. Chitin and its derivative, chitosan, can be recovered from shrimp shell waste (Figure 2) by chemical methods and may yield valuable byproducts for biomedical applications while reducing pollution [33].

Compared to commercial biopolymers, chitosan and chitin extracted from shrimp shells have good antibacterial activity against Gram-negative bacteria (Escherichia coli) [34]. Although waste from shrimp processing can generate commercially valuable biomolecules, including oil enriched in astaxanthin, protein, chitin, and chitosan, biorefineries of shrimp processing waste have not yet been extensively developed [35,36]. Ultrasound also helps produce biopolymers from shrimp shells, reduce protein content and particle size, and preserve beef [37].

Chitosan from fish scales, shrimp, and crab shells also had a higher fat-binding and water-binding capacity than commercial chitosan but lower thermal stability and deacetylation [38]. Artificial neural networks can help establish the best conditions for extracting chitosan from crabshell waste, allowing it to achieve a higher deacetylation degree and improved chitosan properties [39]. The extraction and conversion of seafood waste into valuable commercial products can be carried out, contributing to environmental protection and good human health [40].

2.1.4. Squid and Snail

Chitin derived from squid pens and snail shells represent valuable alternative sources. Squid-derived chitin, primarily β-chitin, exhibits higher solubility and reactivity than α-chitin from crustaceans, favoring applications in nanomedicine. Snail shells offer a terrestrial biomass resource rich in calcium carbonate and chitin, with demonstrated use in scaffolds and antimicrobial films. Though less utilized industrially, these sources are gaining attention due to their distinct physicochemical properties [10,28].

2.2. Chemical Structures of Chitin and Chitosan

Chitin is a linear polysaccharide consisting of mainly N-acetyl-D-glucosamine (GlcNAc) units with β-1.4 glycosidic bonds (Figure 1). Chitosan, with amino (-NH2) and hydroxyl (-OH) functional groups in its chemical structure, makes it a highly reactive and versatile biomaterial that can be targeted to different applications [2,3]. Hydrogen bonding is one of the strongest intermolecular bonds, leading to high crystallinity and mechanical strength [1]. D-glucosamine (GlcN) units interspersed in chitosan exclude chitin, which is supposed to hold more unbound amine sets [41,42].

The presence of two amide groups and extensive intermolecular hydrogen bonding in chitin gives it an orthorhombic structure and reduces its ability to swell while immersed in water [43]. Using lactic acid for shrimp waste lactic acid fermentation associated with the freeze–pump–thaw (FPT) process successfully generated high-quality chitin and chitosan, presenting new applications for this material [44]. While chitin and its derivatives hold promise in tissue engineering, drug delivery, diagnosis, molecular imaging, antimicrobial activity, and wound healing, potential limitations and prospects exist [45].

Chitin and chitosan are eco-friendly biomaterials with distinctive qualities, such as antimicrobial properties, and they are used in a wide range of medical and non-medical applications [46,47]. Shell biorefinery can recycle waste shells to prepare high-value chemicals and materials, bringing potential environmental and economic benefits [48].

Chitosan (Figure 1) is a linear polymeric structure obtained from a chitin molecule containing the repeating unit of β-[1→4]-linked 2-amino-2-deoxy-D-glucose (deacetylated unit) and 2-acetamido-2-deoxy-D-glucose (N-acetylated unit). The presence of amino (-NH2) and hydroxyl (-OH) groups in its chemical structure imparts specific properties and reactivity. Unlike chitin, chitosan has amine groups in D-glucosamine units. In acidic solutions, these groups undergo protonation to form the corresponding (i.e., NH3⁺ ion), making chitosan positively charged and soluble in water at low pH values. Hydroxyl groups on the glucosamine units can bond hydrogen, facilitating their intermolecular interactions to form a gel or film. A higher deacetylation degree (DD) (>50%) promotes solubility in acidic solutions and increases its cationic behavior, both of which are important for biological and chemical applications. Due to protonated amino groups, Chitosan is a cationic polymer, allowing it to interact with negatively charged molecules, like proteins, lipids, and DNA. This property is exploited in drug delivery, gene therapy, and wastewater treatment [1,49,50].

Chitosan’s unique chemical structure is characterized by its linear polycation structure of high charge density, reactive hydroxyl, amino groups, and hydrogen bonding. It is also good in biocompatibility, physical stability, and processability. It can potentially be an antimicrobial agent in food and pharmaceutical preparations, but knowledge of its antimicrobial activity is required to maximize preparations and enhance their activity [51]. Table 2 summarizes a solubility profile [1]. Chitin and chitosan exhibit strong hydrogen bonding and high crystallinity, especially in α-chitin, making them insoluble in most solvents. However, solvents, such as ionic liquids (ILs) and deep eutectic solvents (DES), can disrupt these interactions [31]:

• ILs, like 1-ethyl-3-methylimidazolium acetate ([EMIM][OAc]) and 1-butyl-3-methylimidazolium chloride ([BMIM]Cl), dissolve chitin/chitosan by disrupting the intermolecular hydrogen bonding network, particularly between –OH and –NH2 groups, via ion-dipole interactions [6].
• DES, such as choline chloride:lactic acid or choline chloride:urea mixtures, exhibit similar mechanisms through strong hydrogen bonding with the polymer chains [6].

Some applications post-solubilization include electrospun fibers, hydrogels, and nanoparticle synthesis, with improved dispersibility and functionalization for pharmaceutical uses. Hexafluoroisopropanol (HFIP), though effective in dissolving chitosan, is highly volatile and toxic. It is only used in research-scale applications, such as electrospinning or NMR sample preparation. It requires stringent handling protocols and is not recommended for pharmaceutical formulations [11]. Additional acidic solvents, such as lactic acid, formic acid, and citric acid, promote protonation of amino groups, enhancing chitosan solubility [1,6,12,17,18,44]. EDTA acts as a chelating agent that removes metal ions stabilizing chitin/chitosan networks, facilitating structural loosening and partial solubilization [32,33].

In recent years, various structural modifications and nanostructured chitosan variants have shown great potential for biomedical applications, including tissue engineering, drug delivery, wound healing, and gene therapy.

Table 3 shows a particular product of modified chitosan, its properties, and typical applications, such as chitosan sulfate, thiolate chitosan, and grafted chitosan [1,49,54].

2.3. Rationale for Nanoscale Forms

Chitin and chitosan nanosizing (nanoparticles, nanofibers, or nanocrystals) greatly enhances their surface-to-volume ratio, further developing their physical, chemical, and biological properties. Table 4 describes the main improvements and references supporting them.

The properties of chitin and chitosan are markedly improved by nanosizing, which finds applications in nano-biomedicine, environmental science, and materials engineering. This surface-to-volume ratio enhances mechanical strength, colloidal stability, biocompatibility, and drug delivery efficiency. These modifications highlight nanochitin’s potential for advanced pharmaceutical formulations, including targeted delivery of pharmaceutical drugs and advanced wound dressing [12,48,55].

Due to its biocompatibility and functional groups, chitosan can be utilized to create various multifunctional nanoplatforms. They can be designed to encapsulate therapeutic agents and target moieties. This functionality enables them to act as drug delivery systems, improving efficacy on target cells while reducing toxicity to healthy cells, particularly in the case of cancer cells [56,57,58]. Control of drug release improves biodistribution due to chitosan-based nanoparticles and nanocomposites. It is particularly beneficial in treating cancer, making therapeutic delivery more efficacious [57,58].

Packed with nanochitosan membranes of fibrous membranes of polycaprolactone and water, chitosan was carried to enhance their hydrophilicity, degradation, and sustained antibacterial action. These features identify them as potential candidates for different types of applications, such as wound dressings or transdermal patches that can release drugs in response to pH under different circumstances [59].

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Vega-Baudrit, J.R.; Lopretti, M.; Montes de Oca, G.; Camacho, M.; Batista, D.; Corrales, Y.; Araya, A.; Bahloul, B.; Corvis, Y.; Castillo-Henríquez, L. Nanochitin and Nanochitosan in Pharmaceutical Applications: Innovations, Applications, and Future Perspective. Pharmaceutics 2025, 17, 576. https://doi.org/10.3390/pharmaceutics17050576

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