Advances in Pure Drug Self-Assembled Nanosystems: A Novel Strategy for Combined Cancer Therapy

Abstract

Nanoparticle-based drug delivery systems hold great promise for improving the effectiveness of anti-tumor therapies. However, their clinical translation remains hindered by several significant challenges, including intricate preparation processes, limited drug loading capacity, and concerns regarding potential toxicity. In this context, pure drug-assembled nanosystems (PDANSs) have emerged as a promising alternative, attracting extensive research interest due to their simple preparation methods, high drug loading efficiency, and suitability for large-scale industrial production. This innovative approach presents new opportunities to enhance both the safety and therapeutic efficacy of cancer treatments. This review comprehensively explores recent progress in the application of PDANSs for cancer therapy. It begins by detailing the self-assembly mechanisms and fundamental principles underlying PDANS formation. The discussion then advances to strategies for assembling single pure drug nanoparticles, as well as the co-assembly of multiple drugs. Subsequently, the review addresses the therapeutic potential of PDANSs in combination treatment modalities, encompassing diagnostic and therapeutic applications. These include combinations of chemotherapeutic agents, phototherapeutic approaches, the integration of chemotherapy with phototherapy, and the synergistic use of immunotherapy with other treatment methods. Finally, the review highlights the potential of PDANSs in advancing tumor therapy and their prospects for clinical application, providing key insights for future research aimed at optimizing this technology and broadening its utility in cancer treatment.

Keywords: cancer therapy; carrier-free; combination treatment; nanosystems; pure drug; self-assembly.

Figure 1

Schematic overview of the significant application advancements of pure drug-assembled nanosystems in tumor therapy, including cancer theranostics, combination chemotherapy, combination phototherapy, combination chemotherapy with phototherapy, and the combination of immunotherapy with other therapy. Created with BioRender.com (accessed on 20 November 2024).

Figure 2

Schematic illustration of the self-assembly mechanism of pure drugs. The self-assembly of pure drugs into nanoparticles is primarily driven by non-covalent interactions, including hydrogen bonding, π-π stacking, and hydrophobic interactions. For example, photosensitizers such as chlorin e6 (Ce6) and mitoxantrone, which feature aromatic conjugated structures and an abundance of oxygen and nitrogen atoms, can self-assemble into stable nanoparticles through these interactions. When combined with 660 nm laser irradiation, these nanoparticles enable non-invasive tumor ablation [38]. Similarly, natural compounds like magnolia bark form stable, soluble, carrier-free nanoparticles through hydrogen bonding and hydrophobic interactions, effectively enhancing tumor targeting and therapeutic efficacy [39]. Furthermore, Xiao et al. engineered DOX-PhA nanoparticles via electrostatic self-assembly, leveraging the interaction between the -NH²⁺ group of doxorubicin and the -COO⁻ group of pheophorbide A. This design facilitated a synergistic approach for combined photo/chemotherapy in cancer treatment [40]. A growing body of evidence highlights that π-π stacking, hydrogen bonding, and hydrophobic interactions are key mechanisms underlying the self-assembly of PDANSs. These mechanisms offer a robust and safe framework for the rational design of clinical drug formulations, presenting a promising strategy to enhance therapeutic outcomes. Created with BioRender.com (accessed on 20 December 2024).

Figure 3

Schematic representation of self-assembly of PPa and efficient PDT under laser irradiation. Core-matched PPa nano-assembly was formed by modification of PPa-PEG2K [41].

Figure 4

Distribution of (A) particle size and (B) zeta potential; stability of (C) particle size and (D) zeta potential as a function of time (0 to 21 days) in purified water. Dh, mean hydrodynamic diameter. TEM images of (E) HCPT/Ce6 NRs (molar ratio HCPT: Ce6 = 3:1). SEM images of (F) HCPT/Ce6 NRs [44].

Figure 5

Preparation of cracked cancer cell membranes (CCCMs) and NIR-responsive carrier-free nanosystems (DICNPs) based on packing DOX and ICG co-assembly nanoparticles with CCCMs [45].

Figure 6

Schematic illustration of the preparation of NIR/GSH/pH-sensitive CPT-ss-BBR/ICG NPs and the chemo-photothermal synergistic therapy process of nanodrugs [46].

Figure 7

Schematic diagram of enhanced tumor-targeted imaging and synergistic FUS ablation and chemotherapy using nano therapeutic diagnostic agent A-DPP [58].

Figure 8

Schematic diagram of self-assembly route of CDDP-OLA nanoparticles and their synergistic mechanism [62].

Figure 9

(A) Schematic representation of the preparation of erythrocyte camouflaged Ce6@DiR NPs (Ce6@DiR-M NPs) and its programmed cascade-activatable photothermal–photodynamic therapy for TNBCs with low phototoxicity in normal tissues. (B) In vivo photothermal images under 808 nm laser irradiation (2 W cm⁻², 5 min). (C) H&E stain of skin, spleen, and kidney after the 660 nm laser (5 mW cm⁻² for 1 h) treatment (scale bar represents 50 μm) [69].

Figure 10

Schematic diagram of the preparation of DOG/MOFA/ICG nanoparticles and their action [72].

Figure 11

Schematic illustration of antitumor synergistic immunotherapy mediated by C9SN with laser irradiation via increasing tumor immunogenicity and reversing immunosuppressive tumor microenvironment [76].

Figure 12

Construction of a self-assembled peptide, TpYCR, for stepwise targeting and tandem response-triggered morphological transition [78].

Figure 13

Schematic illustration of the synergistic anti-tumor chemo-immunotherapeutic mechanism of carrier-free MCMD nanoparticles [80].