Structure-Based Varieties of Polymeric Nanocarriers and Influences of Their Physicochemical Properties on Drug Delivery Profiles

Purpose: Drug carriers are as important as drugs themselves, but clinical translation of polymeric nanocarriers (PNCs) remains limited by incomplete understanding of how carrier architecture and physicochemical properties affect loading, circulation, targeting, and release. The review addresses this gap by systematically linking structural varieties of PNCs and their physicochemical properties to drug delivery profiles, and by highlighting multi-stimuli-responsive multi-drug delivery as an emerging direction.

Hypothesis: As a review, this paper does not test a single formal hypothesis. Its central premise is: if PNC structure and physicochemical properties — size, shape, architecture, stability, surface charge, and stimuli-responsiveness — are rationally engineered, then drug loading, bioavailability, targeted delivery, controlled release, and therapeutic efficacy can be improved; incorporating multi-stimuli responsiveness and multi-drug delivery into a single carrier is the future direction for intelligent PNCs.

Aims: Comprehensively investigate structural design-based varieties of PNCs used for drug delivery. - Analyze how physicochemical properties of PNCs influence drug loading, release, biodistribution, and targeting. - Review representative PNC architectures: nanomicelles, nanovesicles/polymersomes, nanogels, nanocapsules, dendrimers, and nanocomposites. - Highlight multi-stimuli-responsive and multi-drug delivery PNCs as new and emerging research directions. - Provide perspectives on challenges and future clinical translation of intelligent PNCs.

Delivery system: PNC architectures: polymeric nanomicelles (20–200 nm), wormlike micelles, polymersomes/nanovesicles (80–150 nm optimal), nanogels, nanocapsules, dendrimers (5–10 nm), nanospheres, and nanocomposites. - Polymer classes: natural and synthetic biodegradable polymers, amphiphilic copolymers (diblock, triblock, graft), stimuli-responsive polymers, and hybrid polymer–lipid systems. - Payloads: small-molecule anticancer drugs (DOX, paclitaxel, camptothecin, cisplatin, gemcitabine, erlotinib), nucleic acids (DNA, mRNA, siRNA), proteins/peptides, vaccines, imaging agents, and adjuvants. - Targeting/stimuli: passive EPR effect; active ligands such as folate, transferrin, RGD, TAT; internal stimuli (pH, redox/GSH, enzymes, glucose, hypoxia); external stimuli (light, temperature, magnetic field, ultrasound). - Multi-drug/multi-stimuli: carriers designed to co-load hydrophilic and hydrophobic drugs and respond to combinations such as pH/redox, pH/temperature, light/pH/reduction, and enzyme/temperature.

Approach: Narrative literature review. No primary experiments are reported. - Evidence base: preclinical in vitro and in vivo studies, selected clinical examples, and publication trend analyses. - Model systems cited: HeLa cells, MCF-7 breast cancer cells, U-87 MG glioblastoma, P388/ADR resistant tumors, pancreatic tumors, B16 melanoma, and various xenograft/orthotopic tumor models. - Clinical context: FDA-approved polymer-based nanomedicines such as Doxil and Onivyde, and clinical-stage PNCs. - Rigor: No systematic review, meta-analysis, or risk-of-bias assessment is provided; evidence is synthesized from cited studies.

Key methods: The review summarizes methods used in cited primary studies rather than presenting new methods: - Nanoparticle characterization: dynamic light scattering for size, zeta potential, morphology, and stability. - Drug loading and release assays under varying pH, redox, temperature, light, and enzymatic conditions. - Cellular uptake, internalization kinetics, cytotoxicity, and biocompatibility assays (MTT, LDH). - In vivo biodistribution, tumor accumulation, blood circulation half-life, and tumor growth inhibition. - Blood–brain barrier permeation studies. - Publication trend analysis using Scopus keywords.

Key results: Representative quantitative findings highlighted in the review: - Aspect ratio and uptake: cylindrical particles with aspect ratio 3 were internalized about 4-fold faster than aspect ratio 1 particles in HeLa cells, despite similar volume and surface charge. - Size-dependent tumor penetration: polymeric micelles of 30 nm permeated poorly permeable pancreatic tumors, whereas 50–100 nm micelles permeated only highly permeable tumors. - Renal clearance and tumor targeting: PEG nanocarriers <12 nm (≤20 kDa) achieved significant tumor targeting with almost negligible nonspecific uptake; >13 nm (>20 kDa) accumulated in liver, lung, and pancreas. - Nanocapsule encapsulation: modified starch nanocapsules containing minocycline hydrochloride had a size of about 90 nm and encapsulation efficiency over 87%. - BBB delivery: PAMAM-PEG-WGA-Tf dendrimer delivered 13.5% of doxorubicin across an in vitro BBB within 2 h, versus 5% for free DOX and 7% for PAMAM-PEG-Tf. - Multi-stimuli trend: publications on multi-stimuli-responsive polymeric carriers increased from 11 in 2012 to 461 in 2020; multi-drug delivery carrier publications also increased but remained much lower, indicating a translational gap.

Interpretation: The authors conclude that PNC architecture and physicochemical properties critically determine drug delivery outcomes, and that intelligent PNCs incorporating multi-stimuli responsiveness and multi-drug delivery in a single carrier represent the future of nanomedicine. They argue that such carriers could reduce the need for personalized delivery systems by performing multiple functions, but clinical translation requires improved in vivo sensitivity/stability, biocompatibility, biodegradability, renal clearance (preferably <40 kDa), and simplified scalable manufacturing.

Limitations: This is a narrative review, not a systematic review or meta-analysis; no quantitative synthesis or risk-of-bias assessment is provided. - Most cited PNC systems remain preclinical; complete clinical translation has not been achieved. - Endogenous stimuli can be inconsistent across patients and tumor types, complicating predictable release. - Multifunctional PNCs often require complicated, multi-step synthesis that hinders large-scale production. - Long-term safety, immunogenicity, batch reproducibility, and regulatory hurdles are not comprehensively addressed. - The review predates more recent advances in mRNA vaccines, CRISPR delivery, and next-generation biodegradable polymers.