Volume 96, June 2024, 105664Author links open overlay panel, , , , , Abstract

Macromolecules, specifically peptides, proteins, nucleic acids (for instance mRNA, siRNA, miRNA), etc. have been anticipated to be exclusive theranostic agents and potentially being applied for the diagnosis and treatment of various dreadful and intractable ailments. Although, macromolecule therapeutics are overpriced, they may alleviate countless downsides of small molecule drugs, as they are certainly tissue-selective, biocompatible, and economically scaled-up. However, unfavorable characteristics viz, rapid degradation in plasma, rapid metabolism, negative-charge density and conventional administration techniques leading to poor patient compliance, restrict the clinical uses of peptide/protein/nucleic acid therapeutics. The fate of macromolecule-based therapeutics depends upon the potential of engineered delivery vehicles that offer enhanced stability of loaded macromolecules from the biological environment and selectively deliver them at the desired site. Recent progress in nanoengineered lipid and polymeric-based delivery systems has broadened the scope of therapeutic targets of macromolecule drugs for various medical conditions. The approval of the first siRNA drug i.e. Patisiran (ONPATTRO™) for the management of transthyretin-regulated amyloidosis is a legendary breakthrough. In this review, we are broadly identifying the current challenges in macromolecule therapeutics and evaluating the advancements in engineered delivery systems for the delivery of biomacromolecules in recent years. We believe that these findings will certainly address the challenges and will encourage the design and development of efficient carrier systems for the delivery of protein/peptide/nucleic acids.

Section snippetsBackground

Since the discovery of insulin in 1921 and its approval for medical use in 1982 [1] (Fig. 1), therapeutic macromolecular drugs such as proteins, peptides, antibodies, and nucleic acids have experienced enduring success stories of managing myriad diseases viz inflammatory diseases, diabetes, cancer, etc [2,3]. They are very selective and potent, have a high safety profile, and show minor side effects vis-à-vis conventional small molecules [1] To date, the US Food and Drug Administration (FDA)

Peptide therapeutics

Owing to the inherent characteristics and pharmacological profiles of peptides, they are considered novel drugs and regarded as an excellent initiator for drug development [6]. Peptides act at an intermediate region of complexity and molar mass and provide several advantages of these two categories. Currently, peptides are used to treat various disorders including metabolic disorders, cancers, cardiovascular diseases. These are also having emerging therapeutic applications in the field of

Biomacromolecules for addressing unmet needs in healthcare

To date, adequate information has been gathered to comprehend that diseases are no longer solitary pieces. Nevertheless, a group of various disorders possess discrete molecular backgrounds. The main question, consequently, is how to contract this challenge where even highly prevalent ailments are becoming a group of disease subsets with diverse treatment responses. Development and availability of new tailor-made diagnostic methodologies to describe the correct scenario of these subsets and

Challenges of biomacromolecules as therapeutic agent

Although, the small-molecular drugs are currently pioneering in the therapeutic market and are the first choice of medical practitioners, biomacromolecules-based therapeutics are progressively exhibiting their huge potential in the management of various tenacious ailments owing to their higher selectivity, higher biological activity, and lesser toxicity [2,47]. However, the clinical applications of these biomacromolecules could be more robust owing to some inevitable confines namely target

Recent therapeutic strategies for biomacromolecule delivery

The needs for potential delivery vehicles to transport the biomacromolecules at curatively appropriate amount to disease sites limits their clinical efficiency. These specially designed drug carriers (Fig. 6) should be able to transport the macromolecules at desired target sites, minimize non-specific adverse effects and prevent systemic and local toxicities. In this context, the progression of nanotechnology has been important in overwhelming countless therapeutic challenges of delivery of

Theranostic applications of biomacromolecules

In spite of the remarkable effectiveness of biomacromolecules as therapeutic agents, they have also undergone transformation to be employed in imaging, and diagnosis of various diseases at an early stage with effective treatment. In cancer theranostics, innumerable preclinical studies of nanotechnology-based systems with entrapped macromolecules have been reported to act selectively on the tumor vasculature for both diagnostic and treatment purposes. These noteworthy results are due in part to

Challenges in the application of nanocarriers for biomacromolecule delivery

In spite of extensive technical progression in the arena of nanobiomedicine, where macromolecules-based nanomedicine has become a new paradigm for diagnosis and treatment of various diseases, their clinical application is in halfway house. Preclinical studies have revealed that lipophilic bioactive/imaging agents could be more efficiently encapsulated in lipid or polymer-based nanocarriers. However, achieving batch to batch uniformity and consistency in terms of loading capacity, particle size,

Regulatory considerations

To date, many peptide/proteins/NA-based formulations and vaccines are available in the market. Therefore, to ensure effective quality control parameters for active pharmaceutical/biological ingredient and/their finished product, the prime challenge is to establish regulatory requirements prior to manufacturing of the finished therapeutic products [120] Before release, the finished product needs to comply with the set specifications of the product which certainly includes several analytical

Outlook and future perspective

The increasing growth of the market for peptide/protein/NA-based therapeutics is evident, with an increasing number of moieties entering pre-clinical and clinical trials. A variety of diseases that are being investigated in clinical trials currently disclose the potential that the peptides/protein/NA hold for biomacromolecule-based therapies. However, peptides/proteins/NA are endowed with inherent physicochemical characteristics which make their site-specific delivery challenging, specifically

CRediT authorship contribution statement

Samarth Kumar: Conceptualization. Neeraj Kumar Garg: Writing – original draft. Ashay Jain: Writing – review & editing. Prachi Pandey: Formal analysis, Data curation. Ajay Khopade: Writing – review & editing. Krutika K. Sawant: Writing – review & editing, Supervision, Conceptualization.

Declaration of competing interest

We declare that we do no have any conflict of interest and this manuscript has not been submitted elsewhere.

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