Drug delivery system refers to the technology that controls the distribution of drugs in the biological body in space, time and dose [1]. It aims to deliver the correct amount of drugs to the specific location at the appropriate time, thereby enhancing drug availability, efficacy, and reducing toxic side effects [2]. Drug delivery systems play an increasingly important role in the drug development process and have become a key factor in determining the effectiveness of a drug. Currently, with the development of new chemical and biological technologies, an increasing number of functional nanomedicine carriers have been developed, such as lipid nanoparticles (LNPs) [3], inorganic nano-formulations [4], polymer micelles [5], peptide-based hydrogels [6,7], and bio-derived carriers. Reasonably designed nanocarriers typically exhibit good biocompatibility and biodegradability, which can ensure the stability, uniformity and specificity of small molecule hydrophobic drugs, nucleic acids, peptides, proteins, antibodies, living cells and so on in specific tissues to ultimately achieve improved disease treatment effect [8,9]. Bioactive peptides have demonstrated significant potential in the treatment of diseases [10,11], regenerative medicine [12,13], immune regulation [[14], [15], [16]], and other related fields. This is attributed to their facile synthesis, high specificity, and favorable biocompatibility [17,18]. However, the inadequate stability and low retention rate of the material remain significant obstacles that impede its broader utilization in vivo and even its translation into clinical practice [19,20]. In order to address these challenges, researchers have dedicated their efforts to the advancement of diverse carriers for the transportation of bioactive peptides [[21], [22], [23], [24], [25]]. Most of these entities are commonly enclosed within nanomaterials or chemically bonded with polymers, resulting in inherent challenges such as reduced encapsulation efficiency and compromised biological functionality.

In recent years, the field of supramolecular chemistry has witnessed a significant surge in research focused on peptide delivery through host-guest interactions [[26], [27], [28], [29], [30]]. Traditional macrocycles, including cyclodextrins [31], calixarenes [32,33], cucurbiturils [34,35], and pillararenes [[36], [37], [38]], typically employ hydrophobic cavities to encapsulate native amino acid residues, thereby facilitating the transportation of integral peptide chains. The aforementioned approach has negative consequences for the effective delivery of bioactive peptides, primarily due to the fact that their activity is contingent upon the binding of amino acid residues to the receptor [39,40]. The correlation between the sequence of amino acids and the specific residues of amino acids in bioactive peptides plays a crucial role in determining the binding affinity to the receptor [[41], [42], [43]]. Therefore, the selection of a bioactive peptide delivery carrier should encompass two key considerations. Firstly, the carrier must possess a robust capacity for complexation with the peptide, thereby enhancing its stability. Secondly, it should aim to preserve the coordination between various amino acid residues, in order to avoid any disruption to the binding of the bioactive peptide with its receptor. Our research group has recently put forward a supramolecular strategy that utilizes host-guest interactions facilitated by large-sized macrocycles [44,45]. This strategy effectively combines two important aspects, and we propose that macrocycles of extended biphen[n]arene could serve as a highly promising candidate for the delivery of bioactive peptides.

The prevalence of brittle fracture resulting from osteoporosis is significantly elevated, particularly among women in the middle-aged and elderly population [46]. Every three seconds, a fracture resulting from osteoporosis takes place on a global scale, with alarming rates of disability and mortality associated with it [47]. Currently, the pharmacological interventions employed for the prevention and treatment of osteoporosis primarily consist of bone resorption inhibitors, bone formation enhancers, drugs with alternative mechanisms, and Chinese traditional medicine [48]. Growth factors are proteins that exhibit specific binding affinity towards cell membrane receptors, thereby regulating cellular growth and function, and are expected to be potential therapeutic agents for the treatment of osteoporosis [49,50]. Platelet-derived growth factor (PDGF) have been identified as highly effective chemokines for bone marrow mesenchymal stem cells (BMSCs), as they have the ability to enhance the migration, proliferation, and osteogenic differentiation of BMSCs [51,52]. Appropriate supplementation of PDGF-BB effectively prevented the development of osteomalacia, while simultaneously promoting trabecular bone formation and enhancing intertrabecular connections [53]. As a result, this intervention significantly improved bone strength and mitigated the effects of glucocorticoid-induced osteoporosis. Previous research has demonstrated that the bioactive peptide Nap-FFGVRKKP (P) serves as a promising analogue of PDGF [54]. However, the in vivo delivery of this peptide continues to pose a pressing challenge. Our previous research has provided clarification on the effectiveness of water-soluble quaterphen[4]arene (4) as a delivery carrier for macromolecular biotoxins. This carrier has demonstrated the ability to achieve supramolecular detoxification through comprehensive complexation [45]. Collectively, the research focused on osteoporosis as the subject of investigation in order to examine the impact of macrocycle carriers on the biological activities of the bioactive peptides being delivered.

The practical application of PDGF delivery typically involves multiple doses and/or supraphysiological concentration dosing to guarantee the appropriate local concentration at the injury site, which simultaneously increases the risk of adverse reactions [[55], [56], [57], [58]]. PDGF is closely related to the occurrence and development of tumors, and is a target for various tumor therapies and a biomarker for prognosis [59]. The overexpression and continuous release of it will induce the occurrence and development of cancer [60,61]. Therefore, for the delivery of PDGF bioactive peptides, the optimal concentration and appropriate dosage are crucial. For this purpose, this study innovatively proposed a strategy involving giant macrocyclic encapsulation of the PDGF bioactive peptide. Employing a giant macrocycle to encapsulate bioactive peptides can prolong the activity of active peptides by improving their stability and tissue retention, and decrease the concentration required to achieve the same therapeutic effect, thereby effectively reducing the risk of adverse reactions and tumor induction. Compared with nanomaterials or polymers for physical packaging or chemical coupling, the present supramolecular delivering system effectively avoids issues such as sudden or delayed release. It also addresses challenges like low encapsulation efficiency and compromised bioactivity commonly encountered by carriers of bioactive peptides. Compared with the traditional host-guest system through encapsulating a single amino acid residue of the bioactive peptide, this system involves encapsulating the entire bioactive peptide using a giant macrocycle, ensuring maximum coordination among amino acid residues to prevent any interference with the binding between the bioactive peptide and its receptor.