Most cancers represents a crucial menace to human survival [1]. Present medical remedies, significantly chemotherapy, focused remedy and photodynamic remedy, proceed to depend on small-molecule medication [2]. Nonetheless, their efficacy is commonly restricted by unfavorable physicochemical properties, insufficient pharmacokinetic profiles, and off-target distribution, which collectively complicate formulation design and cut back in vivo supply effectivity [3], [4]. The emergence of next-generation therapeutics, akin to peptide [5], proteins [6] and nucleic acids [7], has launched further supply challenges, as these macromolecules usually undergo from poor stability, enzymatic susceptibility, and restricted membrane permeability [8]. Nanotechnology-based carriers have tried to beat these drawbacks by enhancing drug solubility and stability, prolonging systemic circulation, and enhancing tumor accumulation. Nonetheless, the in vitro assembled nanostructures usually render them prone to untimely disassembly or useful inactivation underneath dynamic physiological environments. Due to this fact, typical nanoassemblies nonetheless face a number of bottlenecks, together with insufficient concentrating on effectivity, restricted intratumoral penetration, potential carrier-related toxicity, and complexities in scalable manufacturing [9], [10].
To deal with these challenges, in vivo self-assembly has emerged as a transformative technique, impressed by the self-organizing conduct of pure biomacromolecules [11]. The core idea entails the administration of biocompatible molecular “precursors” that stay inert and secure throughout systemic circulation, however bear selective activation inside the tumor microenvironment (TME) in response to endogenous cues (e.g., enzymatic exercise, pH gradients, redox states, receptor overexpression) or exogenous triggers (e.g., mild, temperature, ultrasound, magnetic fields) [12], [13], [14]. The activation induces structural transformations of precursors, akin to modifications in molecular conformation, hydrophobicity/hydrophilicity, or floor cost [15], [16]. These modifications additional drive localized self-assembly by numerous non-covalent intermolecular forces, together with electrostatic interactions, hydrophobic interactions, π-π stacking, and hydrogen bonding, or covalent interactions akin to coordination bonds, condensation reactions, and click on chemistry-mediated cross-linking [17], [18]. This “small-to-large” dynamic course of elegantly integrates the strengths of small molecules and nanomaterials: precursors, by advantage of their minute dimension, obtain deep penetration by the dense tumor stroma, whereas the subsequently shaped assemblies turn out to be successfully trapped and retained inside the tumor, leading to excessive native drug focus and sustained therapeutic publicity.
Such finely tuned processes underscore the crucial significance of rational precursor design for profitable in vivo self-assembly. For optimum therapeutic efficiency, precursors should accumulate selectively at pathological websites, and bear stimulus-triggered molecular transformations that provoke in situ meeting through well-defined intermolecular interactions. Though present critiques have extensively summarized in vivo self-assembled nanomaterials and categorized self-assembly methods in keeping with materials varieties (e.g., peptides, polymers) and particular stimuli (e.g., enzymes, redox), they often undertake descriptive or classificatory approaches and depart a niche in offering a unified and predictable design framework. This evaluate goals to fill this hole by proposing a transformative perspective centered on a modular design technique. In addition to the required energetic pharmaceutical elements, we classify meeting precursors into modular elements based mostly on their useful properties, together with self-assembly modules, response modules, and concentrating on modules. We additional make clear the distinctive organic results achieved by in vivo self-assembly: assembly-induced retention impact, assembly-enhanced binding impact, and assembly-enhanced uptake impact. On this foundation, we talk about advances in therapeutic modalities involving tumor chemotherapy, immune regulation, imaging prognosis, and multi-application remedy (Scheme 1). Total, this evaluate offers rational guiding rules for the event of a brand new technology of in vivo self-assembled nanomedicines, shifting the analysis discipline from purely descriptive classification towards predictive engineering design.
